Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches

ABSTRACT

Applicant hereby submits a substitute abstract that is double spaced.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Patent ApplicationNo. 62/549,528 filed on Aug. 24, 2017 and is a continuation in part ofInternational Application No. PCT/US17/48258, filed on Aug. 23, 2017;which are incorporated herein by reference in their entirety to the fullextent permitted by law.

TECHNICAL FIELD

The present invention relates to the field of transdermal orintracutaneous delivery of pharmaceutical agents, and more particularlyto the delivery of triptans, including zolmitriptan.

BACKGROUND

According to the Migraine Research Foundation, migraine affects 30million men, women and children in the United States. Most migraineslast between four and 24 hours, but some last as long as three days.According to published studies, 63% of migraine patients experiencebetween one and four migraines per month. The prevalence in women (about18%) is on par with asthma and diabetes combined. Approximatelyone-third of those afflicted with migraines have three or more migrainesper month and over half report severe impairment or the need for bedrest. Migraines are most prevalent in the third decade of life,affecting both productivity and quality of life. In surveys of desirableattributes for therapies for migraine, fast relief consistently scoresvery high as one of the most important factors for a migraine therapy.

Acute migraine is an incapacitating headache disorder that ischaracterized by episodic attacks of moderate to severe headachetogether with various combinations of neurological, gastrointestinal andautonomic symptoms. Migraine without aura is usually associated withnausea, vomiting, sensitivity to light, sound or movement, and can lastfor 4-72 hours if untreated. Previously termed “common migraine,”migraine without aura is experienced by approximately 65% of patients.Migraine with aura is experienced by about 15-20% of patients;individuals suffer from transient focal neurological symptoms, usuallyvisual. The visual symptoms are known as an aura. The remainder ofmigraine patients experience both types of migraine.

About a quarter of migraine patients experience one or more episodes perweek. The most unpleasant symptoms associated with acute migraine arenausea and vomiting. The majority (about 90%) of patients experiencenausea; about 70% experience vomiting; and a third typically experienceboth symptoms with every attack.

Cluster headaches are excruciating headaches that recur in a cyclicalpattern (a “cluster”), usually daily, for a period of 1 week or more,usually for six to twelve weeks. In chronic cluster headache, clusterslast for a year or more without remission. Cluster headaches areconsidered to be among the worst headaches known to medical science, andare known to result in pain more severe than migraines. In approximately47% of cases, cluster headache attacks recur at the same time of day ornight, and, in particular, during sleep. Clusters can start at the sametime and have a similar duration year after year. These recurrencepatterns suggest a role of the hypothamlamus (the body's biologicalclock), although the exact cause is unknown.

The pain of a cluster headache is typically on one side (unilateral) orlocalized and is around or above the eye. During an attack, patients maybecome agitated and restless, and they may have trouble resting in oneplace. As patients may prefer to move around, they may rock, sit, pace,crawl, scream in pain, or even bang their head against a hard surface.In some patients, due to the severity and recurrence of clusterheadaches, there is a heightened risk of alcohol and drug abuse,self-injury, and even suicide. Notably, cluster headaches are sometimesreferred to as “suicide headaches.”

Treatment options for cluster headaches are extremely limited. and thereis a strong need for treatments which provide rapid and effectiveresponses. See, e.g., Law et al, Triptans for acute cluster headache,Cochrane Database of Systematic Reviews (2013), Issue 7. While migrainesare different from cluster headaches, it is believed that certaintreatments for migraines including triptans could also be effective forcluster headaches. However, oral and nasal routes of administration arenot particularly effective due to slow absorption rates and the shortduration of the headache. Injected triptans have shown some efficacy,but they are limited by needle phobia, lack of portability, complexpreparation, the requirement for sharps disposal, and safety issuesrelated to needle prick, cutting, and cross contamination infection.

The acute treatment of migraine was revolutionized in 1991 by theintroduction of the triptan class, such as sumatriptan and zolmitriptan.The triptans are serotonin derivatives displaying highly selective andpotent agonist activity at the vascular 5-HT_(1B) receptor and theneuronal 5-HT_(1D) receptor. The mode of action of the triptans ishypothesized to be three-fold: (1) binding of postsynaptic vascular5-HT_(1B) receptors, to stimulate vasoconstriction of meningeal vessels;(2) binding of presynaptic neuronal 5-HT_(1D) receptors, to inhibitrelease of pro-inflammatory neuropeptides; and (3) binding ofpresynaptic neuronal 5-HT_(1D) receptors, to diminish the firing rate intrigeminal neurons and the trigeminal nucleus caudalis (central action).Triptans have similarly shown improved efficacy in treating clusterheadaches over placebos.

Each of the currently available methods of administering triptans,including oral, nasal spray, subcutaneous injection and iontophoreticintracutaneous patch (which is a device that delivers medicine throughthe skin by a low electrical current), has significant disadvantages.Some migraine patients fail to respond consistently to oral triptans,and oral treatments may be ineffectual and/or unpleasant for patientswho are suffering from the nausea, vomiting, or gastric stasis that canbe associated with migraine. Oral, nasal and iontophoretic patch triptanproducts are also characterized by delayed absorption and relativelyslow onset of action causing insufficient relief, especially early inthe episode. This delay is a critical failure in cluster headache, asthe fact that cluster headache episodes often last for 30 minutes orless implies a complete lack of treatment for oral triptans, andsignificantly reduced efficacy for nasal when compared to subcutaneouslydelivered triptans. Cluster headaches are often accompanied by stuffy orrunny nose, which may impact absorption following nasal delivery. Nasalsprays may be unpleasant in taste, and use of injectables can causediscomfort.

Sumatriptan (IMITREX®) has been commercially available in a number ofdosage forms, such as a tablet, subcutaneous (SC) injection, nasal sprayand by transdermal electrophoresis. Oral administration (as a succinate)suffers from poor bioavailability (about 15%) due to poor absorption andpre-systemic metabolism. The time to reach maximum concentration in thebloodstream (T_(max)) after oral tablet administration is about 2 hours.A rapid-release tablet formulation has roughly the same bioavailability,although the T_(max) is achieved on average 10-15 minutes earlier thanthe conventional tablet. When injected, sumatriptan is fast acting(usually within 10 minutes), but the duration of action is lower.Although SC is faster, the tablet formulations of sumatriptan have beenmuch more widely prescribed than the injection because many patients donot like injecting themselves.

The triptans have an excellent safety profile when used appropriatelyand their adverse effect profile is similar to that observed withplacebo in clinical trials. Like other compounds in the triptan class,zolmitriptan has been shown to be effective and well-tolerated inplacebo-controlled clinical trials. It is available in a number ofcommercial formulations (ZOMIG®): (a) a conventional release tablet (2.5mg and 5.0 mg); (b) a “fast melt” orally disintegrating tablet (2.5 mgand 5.0 mg); and (c) a nasal spray (5.0 mg).

The bioavailability of zolmitriptan conventional release tablets hasbeen found to be between 41 and 48%, and administration with foodreduced C_(max) and AUC by 13-16% (Seaber et al., “The absolutebioavailability and metabolic disposition of the novel antimigrainecompound zolmitriptan (311C90),” Br. J. Clin. Pharmacol. 1997; 43(6):579-87; Seaber et al., “The absolute bioavailability and effect of foodon the pharmacokinetics of zolmitriptan in healthy volunteers,” Br. J.Clin. Pharmacol. 1998; 46: 433-439). The T_(max) of the conventionaltablet is about 1.5 hours. Absorption is reported to be lower during anactual migraine attack so the T_(max) may be higher during a migraine.Zolmitriptan is converted to an active N-desmethyl metabolite such thatthe metabolite concentrations are about two-thirds that of zolmitriptan.Because the 5HT_(1B/1D) potency of the metabolite is 2 to 6 times thatof the parent, the metabolite may contribute a substantial portion ofthe overall effect after zolmitriptan administration.

The bioavailability of the orally disintegrating tablets is similar tothat of the conventional tablets but the T_(max) is (somewhatsurprisingly) higher, at about 3 hours for the disintegrating tabletscompared with 1.5 hours for the conventional tablet. The disintegratingtablets may also exacerbate nausea often concomitant with a migraineattack.

Zolmitriptan has significant advantages over other triptans whencontemplated for alternate delivery routes and methods. Only threetriptans, zolmitriptan, naratriptan, and frovatriptan have a lowest oraldose less than 5 mg. However, at this lowest dose, zolmitriptansignificantly outperforms naratriptan in terms of pain relief at 2 hours(62% vs. 49%), and pain freedom at 2 hours (29% vs. 18%). (C. Asseburg,P. Peura, T. Oksanen, J. Turunen, T. Purmonen and J. Martikainen (2012);Cost-effectiveness of oral triptans for acute migraine: Mixed treatmentcomparison. International Journal of Technology Assessment in HealthCare, 28, pp 382-389), and frovatriptan “has the lowest efficacy in2-hour response, 2-hour pain free compared to the other triptans”(Neuropsychiatr Dis Treat. 2008 February; 4(1): 49-54).

Nasal administration of zolmitriptan was used in an attempt to overcomethe disadvantages of oral delivery described above, and doses of 2.5 mgand 5.0 mg have been commercialized. However, the T_(max) ofzolmitriptan is only improved slightly (to about 1.5 hours), and a largeportion of the dose is swallowed and still subject to first passmetabolism.

Other non-oral routes of administration such as transdermaliontophoresis, patches and liquid injectors have the disadvantages ofskin irritation and scarring, pain and inability to deliver atherapeutically effective dose. Subcutaneously injected sumatriptan hasbeen available for years but has never been widely used because it isdifficult to prepare and due to issues related to needle phobia, sharpsdisposal, and accidental pricking, cutting, and cross contamination thatare related to delivery with a needle.

Effectiveness of treatment of migraine with triptans has been shown tobe more dependent on rate of absorption than on dose or plasmaconcentration. More rapid absorption and earlier T_(max) leads to betterpain relief, not just early in a migraine episode but surprisingly evenlater when the plasma concentration from the slower absorbed therapy ishigher. In cluster headache, in addition to the above effect, there is aneed for rapid absorption simply because of the short duration of theheadache event. Rapid absorption can further reduce required applicationtime of a transdermal patch, and lead to more efficient delivery of thepackaged dose, which facilitates reproducibility, for example byreducing variability caused by variation in patch wear time.

Therefore, advantages could be achieved by a therapeutic alternative tocurrently available migraine and cluster headache treatments that: (a)has an onset of action faster than oral and comparable to SCformulations but without issues related to needles; (b) avoids the oralroute that may limit absorption caused by the gastric effects ofmigraine (gastric stasis, nausea and vomiting); (c) mitigates thepotential for food interactions, avoids first-pass metabolism andreduces the potential for drug interactions; (d) is preferred bypatients (rapid onset but not injected or with unpleasant taste/smelle.g., nasal sprays); (e) has lower absorption that reduces triptan sideeffects, e.g., chest constriction while still effective at mitigatingmigraine related headache and nausea; (f) can be conveniently carried bythe patient for use at the first sign of a migraine or cluster headache;and (g) can be quickly, conveniently, and safely self-administered.Additionally, because nausea is present in 60-70% of migraine attacks,it would be advantageous for physicians and patients to have a productthat can be administered without using the gastrointestinal system andnot susceptible to lack of absorption due to emesis. Similarly, stuffyand runny nose in cluster headache may impact the efficacy of nasallydelivered drugs.

Thus, there is a need in the art for a route of administration that canaccommodate the relatively large doses of triptans, such aszolmitriptan, typical of oral doses but lacks the side effects of orallydelivered doses. The present disclosure meets these challenges andneeds, among others. For instance, Applicant has surprisingly discoveredthat transdermal delivery of a triptan, such as zolmitriptan asdescribed herein, can rapidly deliver the relatively large doses ofzolmitriptan typical of oral doses with plasma concentrations in therange of or higher than those seen following oral administration,despite the difficulty of the skin's highly impermeable nature.

There is furthermore a need for a route of triptan administration thathas improved efficacy due to an absorption rate comparable to injectionand is portable and easy to prepare while avoiding the issues of needlephobia, sharps disposal, and accidental pricking, cutting, and crosscontamination that are related to delivery with a needle.

Further, there is a need in the art for an effective method of triptanadministration through transdermal delivery in which the patch can beaccurately and evenly coated, without causing issues of residual drug onthe array or issues of manufacturing inconsistencies, such as unevenformulation coating on a patch or difficulty with formulation stickingto the patch. Many attempts have been made to use transdermalmicroneedle patches for effective drug delivery; however, achievingrapid release of drug from and rapid treatment with microneedle systems,optimizing and developing effective microneedle shapes and sizes, whilealso containing a sufficient dosage of drug has proved elusive.Applicants, through significant development efforts, developed a systemof effective triptan delivery by addressing issues of viscosity, drugloading, surface tension, shape and size of microneedles, and commonmanufacturing defects.

SUMMARY

The present disclosure relates to compositions, devices, methods oftreatment, kits and methods of manufacture of pharmaceutical productsuseful in the treatment of migraines and other conditions, includingcluster headaches. More specifically, the disclosure is directed toadministration of a triptan, such as zolmitriptan, as the activepharmaceutical ingredient to a subject in need thereof. In particular,the present disclosure is directed to transdermally or intracutaneously,or otherwise through the skin, administering a therapeutically effectivedose of the active ingredient that is more rapidly available in thesubject's bloodstream as compared to a therapeutically effective oraldose of the active ingredient, in a format that is easy to use andportable for rapid administration. In one embodiment, the transdermaldelivery of a triptan, such as zolmitriptan, generally comprises a patchassembly having a microprojection member that includes a plurality ofmicroprojections (or “needles” or “microneedles” or “array”) that arecoated with, in fluid contact with a reservoir of, or otherwise comprisethe drug. The patch assembly further comprises an adhesive component,and in a preferred embodiment the microprojection member and adhesivecomponent are mounted in a retainer ring. The microprojections areapplied to the skin to deliver the drug to the bloodstream or, moreparticularly, are adapted to penetrate or pierce the stratum corneum ata depth sufficient to provide a therapeutically effective amount to thebloodstream. In one embodiment, the insertion of the drug-coatedmicroneedles into the skin is controlled by a hand-held applicator thatimparts sufficient impact energy density in less than about 10milliseconds.

Preferably, the microprojection member includes a biocompatible coatingformulation comprising the drug, such as zolmitriptan, in a dosesufficient to provide therapeutic effect. The coating may furthercomprise one or more excipients or carriers to facilitate theadministration of the drug across the skin. For instance, thebiocompatible coating formulation comprises zolmitriptan and awater-soluble carrier that is first applied to the microprojections inliquid form and then dried to form a solid biocompatible coating.

In a preferred embodiment, zolmitriptan, excipients, the coating anddrying process lead to a drug coating that is non-crystalline(amorphous) with a surprisingly rapid dissolution rate. In thisembodiment, the coating, upon its application to the skin via themicroneedles, dissolves at a rate sufficient for rapid uptake of thedrug into the epidermis and bloodstream. In one embodiment, such rate isless than 20 minutes, or less than 15 minutes, or less than 10 minutes,or less than 5 minutes, or less than 2.5 minutes, or less than 1 minute.This rate leads to rapid migraine and cluster headache relief.Preferably, this rapid uptake leads to greater than about 10% ofpatients being pain free in 1 hour after administration, more preferablygreater than about 20% of patients, most preferably about 25% ofpatients or more are pain free. In another embodiment, this rapid uptakeleads to greater than 40% of patients achieving pain relief in 1 hourafter administration, or greater than 50 percent of patients, or about65% of patients or more achieve pain relief 1 hour after administration.Preferably, the drug coating remains amorphous for 1 year, morepreferably 2 years, following gamma or e-beam irradiation.

Such intracutaneous delivery system may be in the form of a device thatis adapted for easy use directly by the patient. For example, the systemmay be a drug-device combination product comprising: (a) a disposablemicroprotrusion member with titanium microneedles that are coated with adrug product formulation and dried, the microprotrusion member beingcentered on an adhesive backing thus forming a patch, and (b) a reusablehandheld applicator that ensures the patch is applied to the skin with adefined application energy sufficient to press the microneedles into thestratum corneum thereby resulting in drug absorption. In one embodiment,the delivery system comprises a patch comprising about 0.2 mg to about10 mg zolmitriptan, or about 1 mg to about 4 mg, or about 1 mg, or about1.9 mg, or about 2 mg, or about 3 mg, or about 3.8 mg, or about 4 mg, orabout 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mgzolmitriptan. In one embodiment, the delivery system is designed todeliver about 0.2 mg to about 10 mg zolmitriptan intracutaneously, orabout 1 mg to about 4 mg, or about 1 mg, or about 1.9 mg, or about 2 mg,or about 3 mg, or about 3.8 mg, or about 4 mg, or about 5 mg, or about 6mg, or about 7 mg, or about 8 mg, or about 9 mg, or more than about 1mg, or more than about 1.9 mg, or more than about 2 mg, or more thanabout 3 mg, or more than about 3.8 mg, or more than about 4 mg, or morethan about 5 mg, or more than about 6 mg, or more than about 7 mg, ormore than about 8 mg or more than about 9 mg zolmitriptan.

In another embodiment, the present disclosure relates to a method fortransdermally or intracutaneously administering a triptan to a patientin need thereof, comprising the steps of: (a) providing a transdermalpatch adapted to intracutaneously deliver a triptan, comprising amicroprojection member having a plurality of microprojections that areadapted to penetrate or pierce the stratum corneum of the patient,wherein the microprojections comprise a biocompatible coating partiallyor fully disposed on the microprojections, the coating comprising atherapeutically effective amount of the triptan; and (b) applying themicroprojection member of the device to the skin of the patient, wherebythe plurality of microprojections penetrate or pierce the stratumcorneum and deliver the triptan to the patient's bloodstream. In oneembodiment, the triptan is zolmitriptan and is coated on themicroprojections in a total amount of approximately 0.2 to 10 mg ofwhich approximately 50%, or 60%, or 65%, or 75%, or 80%, or 85%, or 90%,or 95%, or 100% of such dose reaches the bloodstream of the patientafter administration, preferably wherein more than approximately 50%, or60%, or 65%, or 75%, or 80%, or 85%, or 90%, or 95% of such dose reachesthe bloodstream of the patient after administration.

The present disclosure encompasses a method for treatment or alleviationof migraine or cluster headache in a human patient in need thereof,comprising the transdermal or intracutaneous administration of atherapeutically effective amount of zolmitriptan that produces atherapeutic concentration of zolmitriptan in the bloodstream faster thantherapeutically effective doses administered orally, intranasally,sublingually, or iontophoretically. In one aspect, the method fortreatment or alleviation of migraine or cluster headache in a patientresults in a plasma T_(max) as quick as about 2 minutes and not laterthan about 30-40 minutes in most subjects. In another aspect, the methodresults in a maximum plasma concentration (C_(max)) of zolmitriptan ofless than 50 ng/ml.

In one embodiment, the zolmitriptan-coated microneedle patch asdisclosed herein achieves rapid blood plasma concentrations afterapplication during a migraine or cluster headache attack. Such patchprovides pain freedom and freedom from bothersome migraine or clusterheadache symptoms for at least 45 minutes post administration. Apatient's most bothersome migraine symptom in addition to pain isusually selected from sensitivity to light, particularly bright lights(photophobia), sensitivity to sound, particularly loud sounds(phonophobia), and nausea, although migraines can also be accompanied byvomiting, sensitivity to smell, aura, vision changes, numbness,tingling, weakness, vertigo, feeling lightheaded or dizzy, puffy eyelid,difficulty concentrating, fatigue, diarrhea, constipation, mood changes,food cravings, hives, and/or fever. Common symptoms of cluster headacheinclude excruciating pain, often on one side of the head and generallysituated in or around one eye, but which may radiate to other areas offace, head, neck and shoulders, restlessness, excessive tear productionand redness in the eye on the affected side, stuffy or runny nose,forehead or facial sweating, pale skin (pallor), facial flushing,swelling around the eye on the affected side, and/or drooping eyelid.

Additional embodiments of the present devices, compositions, methods andthe like will be apparent from the following description, drawings,examples, and claims. As can be appreciated from the foregoing andfollowing description, each and every feature described herein, and eachand every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment or aspect. Additional aspects andembodiments are set forth in the following description and claims,particularly when considered in conjunction with the accompanyingexamples and drawings.

REFERENCE TO COLOR DRAWINGS

This application file contains at least one drawing executed in color.Copies of this patent application publication with color drawings willbe provided by the Office upon request and payment of the necessary fee.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing features of embodiments will be more readily understood byreference to the following detailed description, taken with reference tothe accompanying drawings, in which:

FIGS. 1(A) and (B) are scanning electron micrographs (SEM) of MF1663array design coated with 1.9 mg zolmitriptan.

FIG. 2(A)-(B) show views of the patch and the retainer ring structure.(A) provides a top view of the patch and retainer ring. (B) provides abottom perspective view of the patch attached to a retainer ring.

FIG. 3(A)-(B) illustrates the patch assembly, comprised of a patch in aretainer ring. (A) provides a side view of the patch assembly. (B)illustrates an exploded view of a patch assembly.

FIG. 4(A)-(B) illustrates how the used plastic retainer ring is removedfrom the applicator and discarded. The fingers are used to pull the usedretainer ring off the applicator. (A) provides a side view of theretainer ring attached to the applicator. (B) provides a side view ofthe retainer ring separated from the applicator.

FIG. 5(A)-(E) are photographs of the steps for application of the patchof the present invention. (A) illustrates step 1: snap patch assemblyonto applicator. (B) further illustrates step 1 and provides a bottomfront perspective of the patch assembly with the applicator. (C)illustrates step 2: twist applicator cap clockwise from position 1 toposition 2 to unlock for patch application. (D) illustrates step 3:press applicator downward to apply patch to skin. (E) illustrates step4: patch is applied to the patient's skin and the retainer ring remainsattached to the applicator.

FIG. 6(A)-(C) provides in vitro release profiles of ZP-Zolmitriptan M2071.9 mg patches. (A), top left, provides in vitro release profiles ofZP-Zolmitriptan M207 1.9 mg patches that have been E-beam irradiated andstored at RT for 10 months, L/N0164004. (B), top right, provides invitro release profiles of ZP-Zolmitriptan M207 1.9 mg patches that havebeen non-irradiated and stored at 40° C./75% RH for 10 months,L/N0203149-NI. (C), bottom left, provides in vitro release profiles ofZP-Zolmitriptan M207 1.9 mg patches that have been E-beam irradiated andstored at 40° C./75% RH for 10 months, L/N0203149-IR.

FIG. 7 is a line graph of mean zolmitriptan and sumatriptan plasmaconcentrations over time (zero to 24 hours) in normal human volunteers,wherein Treatment A is the M207 system (0.48 mg); Treatment B is theM207 system (0.48 mg×2); Treatment C is the M207 system (1.9 mg);Treatment D is the zolmitriptan (2.5 mg oral tablet); Treatment E is theSumatriptan (6.0 mg SC using auto-injector pen); Treatment F is theZolmitriptan system (1.9 mg×2); and Treatment G is the Zolmitriptansystem (3.8 mg). Sumatriptan was scaled 6/90 to show the sumatriptanconcentration-time profile relative to other treatments.

FIG. 8 is a line graph of mean zolmitriptan and sumatriptan plasmaconcentrations over time (zero to two hours), wherein Treatment A is theM207 system (0.48 mg); Treatment B is the M207 system (0.48 mg×2);Treatment C is the M207 system (1.9 mg); Treatment D is Zolmitriptan(2.5 mg oral tablet); Treatment E is the Sumatriptan (6.0 mg SC usingauto-injector pen); Treatment F is the Zolmitriptan system (1.9 mg×2);and Treatment G is the Zolmitriptan system (3.8 mg). In the graph,sumatriptan was scaled 6/90 to show the sumatriptan concentration-timeprofile relative to other treatments.

FIG. 9 is a line graph of dose linearity of M207 C_(max), for singlepatch and multiple patches, excluding 3.8 mg.

FIG. 10 is a line graph of dose linearity of M207 AUC_(t), for singlepatch and multiple patches, excluding 3.8 mg.

FIG. 11 is a line graph of mean plasma zolmitriptan concentrations infemales over zero to two hours.

FIG. 12 is a line graph of mean plasma zolmitriptan concentrations inmales over zero to two hours.

FIG. 13 is a line graph of mean plasma N-desmethyl zolmitriptanconcentration over zero to two hours.

FIG. 14 is a line graph of mean N-desmethyl zolmitriptan plasmaconcentrations over zero to twenty-four hours.

FIG. 15 is a line graph of dose linearity of M207 C_(max) for singlepatch and multiple patches.

FIG. 16 is a line graph of dose linearity of M207 AUC_(t) for singlepatch and multiple patches.

FIG. 17 is a line graph of dose linearity of M207 AUC_(inf) for singlepatch and multiple patches.

FIG. 18 is a line graph of dose linearity of M207 AUC_(inf) for singlepatch and multiple patches, excluding 3.8 mg patch.

FIG. 19 is a line graph of N-desmethyl zolmitriptan dose linearityC_(max) as a function of M207 dose for single patch and multiplepatches.

FIG. 20 is a line graph of N-desmethyl zolmitriptan dose linearityAUC_(t) as a function of M207 dose for single patch and multiplepatches.

FIG. 21 is a line graph of N-desmethyl zolmitriptan dose linearityAUC_(inf) as a function of M207 dose for single patch and multiplepatches.

FIG. 22 is a line graph of N-desmethyl zolmitriptan dose linearityC_(max) as a function of M207 dose for single patch and multiplepatches, excluding 3.8 mg.

FIG. 23 is a line graph of N-desmethyl zolmitriptan dose linearityAUC_(t) as a function of M207 dose, for single patch and multiplepatches, excluding 3.8 mg.

FIG. 24 is a line graph of N-desmethyl zolmitriptan dose linearityAUC_(inf) as a function of M207 dose, for single patch and multiplepatches, excluding 3.8 mg.

FIG. 25 is a graphical comparison of “% pain free” at 1, 2, and 4 hoursafter treatment.

FIG. 26 is a graphical comparison of “% pain relief” at 1, 2, and 4hours after treatment.

FIG. 27 is a graphical comparison of “% pain free” at 1, 2, and 4 hoursafter treatment.

FIG. 28 is a graphical comparison of “% pain relief” at 1, 2, and 4hours after treatment.

FIG. 29 is a graphical comparison of “% subjects with pain freedom” forup to 4 hours after treatment.

FIG. 30 is a graphical representation of the mean flux results from exvivo human skin samples.

FIG. 31 depicts the interaction of microprojections with the skin, and,specifically, how the microprojections penetrate the stratum corneum foreffective drug delivery.

FIG. 32 demonstrates an embodiment of a microprojection with a shape anddimensions before the microprojection is bent outward from the substrateand coated with drug.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

The various aspects and embodiments will now be fully described herein.These aspects and embodiments may, however, be embodied in manydifferent forms and should not be construed as limiting; rather, theseembodiments are provided so the disclosure will be thorough andcomplete, and will fully convey the scope of the present subject matterto those skilled in the art. All publications, patents and patentapplications cited herein, whether supra or infra, are herebyincorporated by reference in their entirety.

I. INTRODUCTION

Applicant surprisingly found, inter alia, that a dose of zolmitriptantypical of that of an oral delivery was well tolerated in deliveryroutes other than oral delivery, e.g., such as the intracutaneous ortransdermal delivery of zolmitriptan as described herein. In accordancewith this disclosure, the delivery of zolmitriptan generally comprises adelivery system comprising a microprojection member (or system) thatincludes a plurality of microprojections (or array thereof) that areadapted to penetrate or pierce the stratum corneum into the underlyingepidermis layer, or epidermis and dermis layers. Applicant, throughsignificant trial and error and development efforts, customized thetransdermal delivery of zolmitriptan. In one embodiment, themicroprojection member includes a biocompatible coating comprisingzolmitriptan. This system provides superior pharmacokinetics andpharmacodynamics over existing therapies and can be extended to othertriptans useful for treating migraines, cluster headaches, and otherdiseases or conditions.

II. DEFINITIONS

Unless defined otherwise, all terms and phrases used herein include themeanings that the terms and phrases have attained in the art, unless thecontrary is clearly indicated or clearly apparent from the context inwhich the term or phrase is used. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, particular methods andmaterials are now described.

Unless otherwise stated, the use of individual numerical values arestated as approximations as though the values were preceded by the word“about” or “approximately.” Similarly, the numerical values in thevarious ranges specified in this application, unless expressly indicatedotherwise, are stated as approximations as though the minimum andmaximum values within the stated ranges were both preceded by the word“about” or “approximately.” In this manner, variations above and belowthe stated ranges can be used to achieve substantially the same resultsas values within the ranges. As used herein, the terms “about” and“approximately” when referring to a numerical value shall have theirplain and ordinary meanings to a person of ordinary skill in the art towhich the disclosed subject matter is most closely related or the artrelevant to the range or element at issue. The amount of broadening fromthe strict numerical boundary depends upon many factors. For example,some of the factors which may be considered include the criticality ofthe element and/or the effect a given amount of variation will have onthe performance of the claimed subject matter, as well as otherconsiderations known to those of skill in the art. As used herein, theuse of differing amounts of significant digits for different numericalvalues is not meant to limit how the use of the words “about” or“approximately” will serve to broaden a particular numerical value orrange. Thus, as a general matter, “about” or “approximately” broaden thenumerical value. Also, the disclosure of ranges is intended as acontinuous range including every value between the minimum and maximumvalues plus the broadening of the range afforded by the use of the term“about” or “approximately.” Consequently, recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

The term “amorphous” means a non-crystalline solid, i.e., a solid thatlacks the long-range order that is characteristic of a crystal.

The term “area under the curve” or “AUC” means the area under the curve(mathematically known as definite integral) in a plot of concentrationof drug in blood plasma against time. Typically, the area is computedstarting at the time the drug is administered and ending when theconcentration in plasma is negligible. In practice, the drugconcentration is measured at certain discrete points in time and thetrapezoidal rule is used to estimate AUC.

The term “biocompatible coating,” as used herein, means and includes acoating formed from a “coating formulation” that has sufficient adhesioncharacteristics and no (or minimal) adverse interactions with thebiologically active agent (a/k/a active pharmaceutical ingredient, ortherapeutic agent, or drug).

The term “bioequivalent,” as used herein, denotes a scientific basis onwhich two or more pharmaceutical products, compositions or methodscontaining same active ingredient are compared with one another.“Bioequivalence” means the absence of a significant difference in therate and extent to which the active agent in pharmaceutical equivalentsor pharmaceutical alternatives becomes available at the site of actionwhen administered in an appropriately designed study. Bioequivalence canbe determined by an in vivo study comparing a pharmacokinetic parameterfor the two compositions. Parameters often used in bioequivalencestudies are T_(max), C_(max), AUC_(0-inf), AUC_(0-t). In the presentcontext, substantial bioequivalence of two compositions or products isestablished by 90% confidence intervals (CI) of between 0.80 and 1.25for AUC and C_(max).

The term “cluster” as used herein refers to a series of recurringcluster headaches. Cluster duration is usually from one week to oneyear, although in chronic cluster headache the duration exceeds oneyear. The end of a cluster is identified by at least 1 month ofremission.

The term “cluster headache” as used herein refers to a conditioncharacterized by excruciating headache pain that recurs, usually daily(although bouts may recur up to 8 times per day), for a period of a weekor longer. Cluster headaches pain is usually localized on one side ofthe head (“unilateral”) usually the same side although in some patientsthe side can vary. The pain usually reaches full intensity in under 10minutes and lasts for between 15 minutes and 3 hours (usually between 30and 60 minutes). Because of the rapid onset of symptoms and shortduration, treatment via a route by which the drug is rapidly absorbed isrequired.

The term “coating formulation,” as used herein, means and includes afreely flowing composition or mixture, which is employed to coat adelivery surface, including one or more microprojections and/or arraysthereof.

The term “degradation,” as used herein, means the purity of thebiological agent decreases from an initial time point.

The term “desiccant,” as used herein, means an agent that absorbs water,usually a chemical agent.

The term “deteriorate,” as used herein, means that the biologicallyactive agent is diminished or impaired in quality, character, or value.

The term “electrotransport” refers, in general, to the passage of abeneficial agent, e.g., a drug or drug precursor, through a body surfacesuch as skin, mucous membranes, nails, and the like. The transport ofthe agent is induced or enhanced by the application of an electricalpotential, which results in the application of electric current, whichdelivers or enhances delivery of the agent, or, for “reverse”electrotransport, samples or enhances sampling of the agent. Theelectrotransport of the agents into or out of the human body may beattained in various manners.

The term “half life” as used herein refers to the time required for adrug's blood or plasma concentration to decrease by one half. Thisdecrease in drug concentration is a reflection of its excretion orelimination after absorption is complete and distribution has reached anequilibrium or quasi-equilibrium state. The half life of a drug in theblood may be determined graphically from a pharmacokinetic plot of adrug's blood-concentration time plot, typically after intravenousadministration to a sample population. The half life can also bedetermined using mathematical calculations that are well known in theart. Further, as used herein the term “half life” also includes the“apparent half-life” of a drug. The apparent half life may be acomposite number that accounts for contributions from other processesbesides elimination, such as absorption, reuptake, or enterohepaticrecycling.

The term “headache pain scale” as used herein means a scale used toallow patients to quantify their level of pain. Preferably a scale of0-3 is used, wherein severe pain has a pain score of 3, moderate painhas a score of 2, mild pain has a score of 1, and no pain (also referredto as “pain freedom”) has a score of 0.

The word “intracutaneous” as used herein, is a generic term that refersto delivery of an active agent (e.g., a therapeutic agent, such as adrug, pharmaceutical, peptide, polypeptide or protein) through the skinto the local tissue or systemic circulatory system without substantialcutting or penetration of the skin, such as cutting with a surgicalknife or piercing the skin with a hypodermic needle. Intracutaneousagent delivery includes delivery via passive diffusion as well asdelivery based upon external energy sources, such as electricity (e.g.,iontophoresis) and ultrasound (e.g., phonophoresis).

The term “intracutaneous flux,” as used herein, means the rate ofintracutaneous delivery of a drug.

The term “microprojection member” or “microneedle array,” and the likeas used herein, generally connotes a microprojection grouping comprisinga plurality of microprojections, preferably arranged in an array, forpenetrating or piercing the stratum corneum. The microprojection membercan be formed by etching or punching a plurality of microprojectionsfrom a thin sheet of metal or other rigid material, and folding orbending the microprojections out of the plane of the sheet to form aconfiguration. The microprojection member could alternatively befabricated with other materials, including plastics or polymers, such aspolyetheretherketone (PEEK). The microprojection member can be formed inother known techniques, such as injecting molding or micro-molding,microelectromechanical systems (MEMS), or by forming one or more stripshaving microprojections along an edge of each of the strip(s), asdisclosed in U.S. Pat. Nos. 6,083,196; 6,091,975; 6,050,988; 6,855,131;8,753,318; 9,387,315; 9,192,749; 7,963,935; 7,556,821; 9,295,714;8,361,022; 8,633,159; 7,419,481; 7,131,960; 7,798,987; 7,097,631;9,421,351; 6,953,589; 6,322,808; 6,083,196; 6,855,372; 7,435,299;7,087,035; 7,184,826; 7,537,795; 8,663,155, and U.S. Pub. Nos.US20080039775; US20150038897; US20160074644; and US20020016562. As willbe appreciated by one having ordinary skill in the art, when amicroprojection array is employed, the dose of the therapeutic agentthat is delivered can also be varied or manipulated by altering themicroprojection array size, density, etc.

The term “microprojections” and “microneedles,” as used interchangeablyherein, refers to piercing elements that are adapted to penetrate,pierce or cut into and/or through the stratum corneum into theunderlying epidermis layer, or epidermis and dermis layers, of the skinof a living animal, particularly a mammal and, more particularly, ahuman. In one embodiment of the invention, the piercing elements have aprojection length less than 1000 microns. In a further embodiment, thepiercing elements have a projection length of less than 500 microns,more preferably less than 400 microns. The microprojections further havea width in the range of approximately 25 to 500 microns and a thicknessin the range of approximately 10 to 100 microns. The microprojectionsmay be formed in different shapes, such as needles, blades, pins,punches, and combinations thereof.

The terms “minimize” or “alleviate” as used herein means reduce.

“Most bothersome other symptom” means a symptom, usually a migrainesymptom, that is most bothersome to a patient, in addition to pain.Preferably, a most bothersome other symptom is identified by a patientat the start of a clinical trial. Usually, most bothersome other symptomis selected from nausea, photophonia, and phonophobia.

“Most bothersome other symptom freedom” means the patient reports anabsence of the most bothersome other symptom at one or morepre-specified times after drug administration. Preferred times formigraine patients are 1 hour, 2 hours, and 4 hours. Preferred times forcluster headache patients are 15 minutes and 30 minutes.

“Nausea freedom” means the patient reports the absence of nausea at apre-specified time period after drug administration.

“Optional” or “optionally” means that the subsequently describedelement, component or circumstance may or may not occur, so that thedescription includes instances where the element, component, orcircumstance occurs and instances where it does not.

“Pain freedom” means the patient reports an absence of headache pain(headache pain score=0) at one or more pre-specified time after drugadministration. Preferred times for migraine patients are 1 hour, 2hours, and 4 hours. Preferred times for cluster headache patients are 15minutes and 30 minutes.

“Pain relief” means the patient reports a reduction in headache pain, areduction from moderate or severe pain (headache pain score=3 or 2) tomild or no pain (headache pain score=1 or 0), at one or morepre-specified time period after drug administration. Preferred times formigraine patients are 1 hour, 2 hours, and 4 hours. Preferred times forcluster headache patients are 15 minutes and 30 minutes.

“Phonophobia” refers to a fear of or aversion to sounds, especially loudsounds.

“Phonophobia freedom” means the patient reports the absence ofphonophobia at a pre-specified time period after drug administration.

“Photophobia” refers to increased, often painful sensitivity to light,especially bright light.

“Photophobia freedom” means the patient reports the absence ofphotophobia at a pre-specified time period after drug administration.

“Partial AUC” means an area under the drug concentration-time curve(AUC) calculated using linear trapezoidal summation for a specifiedinterval of time, for example, AUC(0-1 hr), AUC(0-2 hr), AUC(0-4 hr),AUC(0-6 hr), AUC(0-8 hr) etc.

A drug “release rate,” as used herein, refers to the quantity of drugreleased from a dosage form or pharmaceutical composition per unit time,e.g., milligrams of drug released per hour (mg/hr). Drug release ratesfor drug dosage forms are typically measured as an in vitro rate ofdissolution, i.e., a quantity of drug released from the dosage form orpharmaceutical composition per unit time measured under appropriateconditions and in a suitable fluid.

The term “stable,” as used herein, refers to an agent formulation, meansthe agent formulation is not subject to undue chemical or physicalchange, including decomposition, breakdown, or inactivation. “Stable” asused herein, refers to a coating also means mechanically stable, i.e.,not subject to undue displacement or loss from the surface upon whichthe coating is deposited.

The terms “subject” or “patient” are used interchangeably herein andrefer to a vertebrate, preferably a mammal. Mammals include, but are notlimited to, humans.

The terms “therapeutic-effective” or “therapeutically-effective amount,”as used herein, refer to the amount of the biologically active agentneeded to stimulate or initiate the desired beneficial result. Theamount of the biologically active agent employed in the coatings of theinvention will be that amount necessary to deliver an amount of thebiologically active agent needed to achieve the desired result. Inpractice, this will vary widely depending upon the particularbiologically active agent being delivered, the site of delivery, and thedissolution and release kinetics for delivery of the biologically activeagent into skin tissues.

The term “transdermal,” as used herein, means the delivery of an agentinto and/or through the skin for local or systemic therapy.

The term “transdermal flux,” as used herein, means the rate oftransdermal delivery.

The term “T_(max)” refers to the time from the start of delivery toC_(max), the maximum plasma concentration of the biologically activeagent.

The term “package” or “packaging” will be understood to also includereference to “storage” or “storing.”

The term “zolmitriptan” includes, without limitation, zolmitriptansalts, simple derivatives of zolmitriptan and closely related molecules.

III. INTRACUTANEOUS DELIVERY SYSTEM

In one embodiment, the intracutaneous delivery system is a transdermalor intracutaneous drug delivery technology which comprises a disposablepatch comprised of a microprojection member centered on an adhesivebacking. The microprojection member comprises titanium (or other rigidmaterial, including a plastic or polymeric material likepolyetheretherketone (PEEK)) microneedles that are coated with a drydrug product formulation. The patch is mounted in a retainer ring toform the patch assembly. The patch assembly is removably mounted in ahandheld applicator to form the intracutaneous delivery system. Theapplicator ensures that the patch is applied with a defined applicationspeed and energy to the site of intracutaneous administration. Theapplicator may be designed for single use or be reusable.

More particularly, the patch can comprise an array of about 3 to 6 cm²of titanium microneedles approximately 200-350 microns long, coated witha hydrophilic formulation of the relevant drug, and attached to anadhesive backing. The maximum amount of active drug that can be coatedon a patch's microneedle array depends on the active moiety of the drugformulation, the weight of the excipients in the drug formulation, andthe coatable surface area of the microneedle array. For example, patcheswith about 1 cm², 2 cm², 3 cm², 4 cm², 5 cm², and 6 cm² microneedlearrays may be employed. The patch is applied with a hand-held applicatorthat presses the microneedles into the skin to a substantially uniformdepth in each application, close to the capillary bed, allowing fordissolution and absorption of the drug coating, yet short of the nerveendings in the skin. The typical patch wear time is about 15 to 45minutes or less, decreasing the potential for skin irritation. Nominalapplicator energies of about 0.20 to 0.60 joules are generally able toachieve a good balance between sensation on impact and arraypenetration. The actual kinetic energy at the moment of impact may beless than these nominal values due to incomplete extension of theapplicator's spring, energy loss from breaking away the patch from itsretainer ring, and other losses, which may comprise approximately total25% of the nominal.

A. Array Design

A number of variables play a role in the type of array utilized for aparticular active agent. For example, different shapes (e.g., shapessimilar to an arrowhead as shown in FIG. 31, hook, conical, or theWashington monument, FIG. 1(A)-(B)) may enable higher drug loadingcapacity, while the length of the microprojections may be increased toprovide more driving force for penetration. The stratum corneum has athickness of about 10-40 μm, and microprojections must have an adequatesize, thickness, and shape to penetrate and effect drug delivery throughthe stratum corneum. FIG. 31, not drawn to scale, demonstrates how anarray interacts with the skin, such that the microprojections penetratethe stratum corneum and the substrate interfaces with the surface of theskin. It is advantageous to achieve a thicker coating on themicroprojections, which will penetrate the stratum corneum, whileavoiding applying coating to the substrate or the base (“streets”) ofthe array, which will not penetrate the stratum corneum. A largersurface area allows for a thicker coating without extending to the baseor streets of the array. The coating is applied only to themicroprojections. Further, the higher penetration force required for amore bulky projection with coating may be compensated by a longer lengthand lower density of projections per cm².

Exemplary intracutaneous delivery systems that may be used in thepresent disclosure include the drug delivery technologies described inU.S. Pat. Nos. 6,083,196; 6,091,975; 6,050,988; 6,855,131; 8,753,318;9,387,315; 9,192,749; 7,963,935; 7,556,821; 9,295,714; 8,361,022;8,633,159; 7,419,481; 7,131,960; 7,798,987; 7,097,631; 9,421,351;6,953,589; 6,322,808; 6,083,196; 6,855,372; 7,435,299; 7,087,035;7,184,826; 7,537,795; 8,663,155, and U.S. Pub. Nos. US20080039775;US20150038897; US20160074644; and US20020016562. The disclosed systemsand apparatus employ piercing elements of various shapes and sizes topierce the outermost layer (i.e., the stratum corneum) of the skin, andthus enhance the agent flux. The piercing elements generally extendperpendicularly from a thin, flat substrate member, such as a pad orsheet. The piercing elements are typically small, some having amicroprojection length of only about 25 to 400 microns and amicroprojection thickness of about 5 to 50 microns. These tinypiercing/cutting elements make correspondingly smallmicroslits/microcuts in the stratum corneum for enhancedtransdermal/intracutaneous agent delivery. The active agent to bedelivered is associated with one or more of the microprojections,preferably by coating the microprojections with a triptan- orzolmitriptan-based formulation to form a solid, dry coating, oroptionally, by the use of a reservoir that communicates with the stratumcorneum after the microslits are formed, or by forming themicroprojections from solid triptan-based formulations that dissolveafter application. The microprojections can be solid or can be hollow,and can further include device features adapted to receive and/orenhance the volume of the coating, such as apertures, grooves, surfaceirregularities or similar modifications, wherein the features provideincreased surface area upon which a greater amount of coating can bedeposited. The microneedles may be constructed out of stainless steel,titanium, nickel titanium alloys, or similar biocompatible materials,such as polymeric materials.

The present disclosure therefore encompasses patches and microneedlearrays having the following features:

-   -   Patch size: About 1 to 20 cm², or about 2 to 15 cm², or about 4        to 11 cm², or about 5 cm², or about 10 cm².    -   Substrate size: About 0.5 to 10 cm², or about 2 to 8 cm², or        about 3 to 6 cm², or about 3 cm², or about 3.13 cm², or about 6        cm².    -   Array size: About 0.5 to 10 cm², or about 2 to 8 cm², or about        2.5 to 6 cm², or about 2.7 cm², or about 5.5 cm². or about 2.74        cm², or about 5.48 cm².    -   Density (microprojections/cm²): At least about 10        microprojections/cm², or in the range of about 200 to 2000        microprojections/cm², or about 500 to 1000 microprojections/cm²,        or about 650 to 800 microprojections/cm², or approximately 725        microprojections/cm²    -   Number of microprojections/array: About 100 to 4000, or about        1000 to 3000, or about or about 1500 to 2500, or about 1900 to        2100, or about 2000, or about 1987, or about 200 to 8000, or        about 3000 to 5000, or about or about 3500 to 4500, or about        4900 to 4100, or about 4000, or about 3974.    -   Microprojection length: About 25 to 600 microns, or about 100 to        500 microns, or about 300 to 450 microns, or about 320 to 410        microns, or about 340 microns, or about 390 microns, or about        387 microns. In other embodiments, the length is less than 1000        microns, or less than 700 microns, or less than 500 microns.        Accordingly, the microneedles penetrate the skin to about 25 to        1000 microns.    -   Tip length: About 100 to 250 microns, or about 130 to about 200        microns, or about 150 to 180 microns, or about 160 to 170        microns, or about 165 microns.    -   Microprojection width: About 10 to 500 microns, or about 50 to        300 microns, or about 75 to 200 microns, or about 90 to 160        microns, or about 250 to 400 microns, or about 300 microns, or        about 100 microns, or about 110 microns, or about 120 microns,        or about 130 microns, or about 140 microns, or about 150 microns    -   Microprojection thickness: about 1 micron to about 500 microns,        or about 5 microns to 300 microns, or about 10 microns to 100        microns, or about 10 microns to 50 microns, or about 20 microns        to 30 microns, or about 25 microns.    -   Tip angle: about 10-70 degrees, or about 20-60 degrees or about        30 to 50 degrees, or about 35 to 45 degrees, or about 40        degrees.    -   Total active agent per array: About 0.1 mg to 10 mg, or about        0.5 mg to 5 mg, or about 1 mg to 4 mg, or about 1 mg, or about        1.9 mg, or about 3.8 mg.    -   Amount of inactive ingredient per array: About 0.1 to 10 mg, or        about 0.2 to 4 mg, or about 0.3 mg to 2 mg, or about 0.6 mg, or        about 0.63 mg, or about 1.3 mg, or about 1.26 mg. Alternatively,        the amount of inactive ingredient is from one to three times        less than the active agent, or from about 0.033 mg to about 3.33        mg.    -   Coating Thickness: about 100 μm to about 500 μm, or about 200 μm        to about 350 μm, or about 250 μm to about 290 μm, or about 270        μm.    -   Active agent per microprojection: About 0.01 to about 100 μg, or        about 0.1 to 10 μg, or about 0.5 to 2 μg, or about 1 μg, or        about 0.96 μg.

A particularly preferred embodiment has a patch area of about 5 cm²adhered to a titanium substrate with an area of about 3.1 cm² and athickness of about 25 μm. The substrate is comprised of amicroprojection array with an area of about 2.74 cm² containing about1987 microprojections at a density of about 725 microprojections/cm².The dry formulation contained on each microprojection may have theapproximate shape of an American football with a thickness that tapersdown from a maximum of about 270 μm and consists of about 0.96 μg ofzolmitriptan and about 0.32 of tartaric acid, or about 1.9 mg ofzolmitriptan and about 0.63 mg of tartaric acid per patch.

FIG. 32 demonstrates the shape of the microprojection, in a preferredembodiment, prior to bending (forming). Array forming is a process thatbends the individual microprojections at right angles to the plane ofthe substrate. An array is placed over the forming tool, which containscavities that are registered with the microprojections. An elastomericforming disk is placed on top of the array and forced under pressureinto the cavities in the forming tool. The elastomer flows into thecavities, causing the microprojections to be bent to the desired angle.The use of the elastomer has the advantage that no careful registrationof the forming disk to the microprojections and the cavities is requiredin order to have effective array forming. As shown in FIG. 32, themicroprojections may be substantially rectangular, with a width of about120±13 μm and a thickness of about 25.4±2.5 μm. The microprojections endwith a triangular tip to facilitate penetration. The tip has an angle of40±5 degrees, and is about 165±25 microns long. Prior to bending(forming) out from the substrate, the microprojections have a length ofabout 387±13 μm, and after bending, they protrude perpendicular to thesubstrate about 340 μm.

Another preferred embodiment has a patch area of about 5 cm² adhered toa titanium substrate of about 6 cm² to and a thickness of about 25 μm.The substrate is comprised of an array with an area of about 5.5 cm²containing about 4000 microprojections at a density of about 725microprojections/cm². The dry formulation contained on eachmicroprojection is in the approximate shape of an American football witha thickness that tapers down from a maximum of about 270 and consists ofabout 0.96 μg of zolmitriptan and about 0.32 of tartaric acid, or about3.8 mg of zolmitriptan and about 1.3 mg of tartaric acid per patch. Themicroprojections have a length of about 387±13 μm, a width of about120±13 μm, and a thickness of about 25.4±2.5 μm. The microprojectionsare rectangular, with a triangular tip to facilitate penetration. Thetip has an angle of 40±5 degrees, and is about 165±25 microns long.

The exact combination of bulk, length, and density that produces thedesired penetration will vary, and may depend on the drug, its dose, thedisease or condition to be treated and the frequency of administration.Thus, the drug delivery efficiency of a particular array (i.e., theamount of drug delivered to the bloodstream) will vary between about 40%to 100%, or about 40%, or about 50%, or about 60%, or about 70%, orabout 80%, or about 90%, or about 100%.

B. Impact Applicator

As illustrated in FIGS. 4(A)-(B), 5(A)-(E), the intracutaneous drugdelivery system of the present disclosure may further comprise an impactapplicator having a body and a piston movable within the body, whereinthe surface of the piston impacts the patch against the skin causing themicroprojections to pierce the stratum corneum. The applicator isadapted to apply the microneedle array to the stratum corneum with animpact energy density of at least 0.05 joules per cm² in 10 millisecondsor less, or about 0.26 joules per cm² in 10 milliseconds or less, orabout 0.52 joules per cm² in 10 milliseconds or less.

As illustrated in FIGS. 2(A) and 2(B), the intracutaneous deliverysystem comprises a patch having an adhesive backing on one surface and ashiny metal surface on the other side comprised of the array ofdrug-coated microneedles. The patch may be applied to the skin bypressing the shiny metal surface against the skin either manually, orpreferably by an applicator. Preferably, the applicator applies thepatch to the skin with an impact energy density of 0.26 joules per cm²in 10 milliseconds or less. As shown on FIGS. 2A, 2B, 3A and 3B, thepatch may be connected to and supported by a retainer ring structureforming a patch assembly. The retainer ring is adapted to fit onto theimpact adaptor and removably attach the patch to the applicator. Theretainer ring structure may comprise an inner ring and outer ring, whichare designed to receive the adhesive patch and microneedle array. FIGS.5(A)-(E) demonstrate one embodiment of the claimed invention, in whichthe user facilitates the connection of the impact applicator to theretainer ring, which is already loaded with the patch and themicroneedle array. As shown, once the retainer ring and impactapplicator are connected, a user can unlock the impact applicator bytwisting the applicator cap. FIG. 5(C) shows that the user may thenpress the applicator downward on the skin to dispense the patch andapply it to the skin. The patch will removably attach to the patient'sskin, and the retainer ring remains attached to the applicator. As shownin FIGS. 4(A) and 4(B), the retainer ring reversibly attaches to theimpact applicator such that the impact applicator can be reused duringsubsequent dosing events with additional patch assemblies andpotentially for other active ingredients and disease states.

In another embodiment, the patch and applicator are supplied as asingle, integrated unit, with packaging that ensures the stability andsterility of the formulation. The user removes the system from thepackaging and applies the patch much as described above. The usedapplicator is then disposed of. This embodiment, while somewhat highercost per dose, provides a system that is less complex, smaller, lighter,and easier to use.

The present disclosure can also be employed in conjunction with a widevariety of active transdermal systems (as opposed to passive, manualintracutaneous delivery devices described herein), as the disclosure isnot limited in any way in this regard.

Some active transdermal systems utilize electrotransport. Illustrativeelectrotransport drug delivery systems are disclosed in U.S. Pat. Nos.5,147,296; 5,080,646; 5,169,382 and 5,169,383, the disclosures of whichare incorporated by reference herein in their entirety. One widely usedelectrotransport process, iontophoresis, involves the electricallyinduced transport of charged ions. Electroosmosis, another type ofelectrotransport process involved in the transdermal transport ofuncharged or neutrally charged molecules (e.g., transdermal sampling ofglucose), involves the movement of a solvent with the agent through amembrane under the influence of an electric field. Electroporation,still another type of electrotransport, involves the passage of an agentthrough pores formed by applying an electrical pulse, a high voltagepulse, to a membrane. In many instances, more than one of the notedprocesses may be occurring simultaneously to different extents.Accordingly, the term “electrotransport” is given herein its broadestreasonable interpretation, to include the electrically induced orenhanced transport of at least one charged or uncharged agent, ormixtures thereof, regardless of the specific mechanism(s) by which theagent is actually being transported with.

In addition, any other transport enhancing method, including but notlimited to chemical penetration enhancement, laser ablation, heat,ultrasound, or piezoelectric devices, can be used in conjunction withthe disclosure herein.

IV. ACTIVE AGENTS AND BIOCOMPATIBLE COATING

The coating formulations applied to the microprojection member describedabove to form solid coatings are comprised of a liquid, preferably anaqueous formulation having at least one biologically active agent, whichcan be dissolved within a biocompatible carrier or suspended within thecarrier. The biologically active agent may be a triptan, includingzolmitriptan, sumatriptan, rizatriptan, naratriptan, eletriptan,almotriptan, frovatriptan, avitriptan, and donitriptan, andpharmaceutically acceptable salts, fragments, analogs, or prodrugsthereof. Preferably, the biologically active agent is zolmitriptan.

Examples of pharmaceutically acceptable salts include, withoutlimitation, acetate, propionate, butyrate, pentanoate, hexanoate,heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate,glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate,tricarballylate, malonate, adipate, citraconate, glutarate, itaconate,mesaconate, citramalate, dimethylolpropionate, tiglate, glycerate,methacrylate, isocrotonate, β-hydroxibutyrate, crotonate, angelate,hydracrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate,lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate,benzene sulfonate, methane sulfonate, sulfate and sulfonate.

The concentration of biologically active ingredient and excipients mustbe carefully controlled to achieve the desired amount of the activeingredient with an acceptable coating thickness, avoid wicking of thecoating formulation onto the base of the microneedle array, maintain theuniformity of the coating, and ensure stability. In one embodiment, theactive agent is present in the coating formulation at a concentration ofbetween about 1% w/w to about 60% w/w, preferably between about 15% and60%, or more preferably between 35% and 45%. The formulation may furthercomprise an acid at a concentration of between about 0.1% w/w to about20% w/w. Such acid may be selected from tartaric acid, citric acid,succinic acid, malic acid, maleic acid, ascorbic acid, lactic acid,hydrochloric acid, either individually or in combination. In anotherembodiment, in the coating formulation, the active agent to acid ratiois about 1:1, about 2:1, about 3:1, about 4:1, or about 5:1. The presentdisclosure further encompasses a coating formulation comprising about33% w/w zolmitriptan base and about 11% w/w tartaric acid. In someembodiments, the acid is one of tartaric acid, citric acid, succinicacid, malic acid or maleic acid, and is present in an amount of about0.33% to 10% w/w, or about 8.33% to about 16.67% w/w, or about 13.33%w/w, or about 15% w/w, or about 6.67% w/w. In some embodiments, thecoating formulation comprises 45% w/w of the active agent, 15% w/w ofthe acid, and 40% w/w of water.

Surfactants may be included in the coating formulation. Surfactantssuitable for inclusion in the coating formulations include, but are notlimited to, polysorbate 20 and polysorbate 80. Surfactants are commonlyused to improve drug delivery as penetration enhancers. However,Applicant found that surfactants resulted in undulations in the coatingformulation, which is indicative of an uneven film and is highlydisadvantageous. Applicant found that the need for surfactants and otherpenetration enhancers can be avoided through the use of the claimedinvention—specifically, through the claimed zolmitriptan transdermaldelivery patches. Furthermore, Applicant surprisingly found thatmicroneedle coating avoided wicking, and the coating sufficientlyadhered to the microprojections during the manufacturing process of themicroneedle arrays, despite the lack of a surfactant.

Antioxidants may be included in the coating formulation. Antioxidantssuitable for inclusion in the coating formulations include, but are notlimited to, methionine, ascorbic acid, and EDTA.

The coating formulation further comprises a liquid, preferably water, inan amount sufficient (qs ad) to bring the formulation to 100% prior tobeing dried onto the microneedles. The pH of the liquid coatingformulation may be below about pH 8. In other cases, the pH is betweenabout pH 3 and 7.4, or between about pH 3.5 to 4.5.

Representative examples of liquid coating formulations according to thepresent disclosure are set forth in Table 1 below. The coatingsgenerally contain at least one acid.

TABLE 1 Coating Formulations Ingredient* 1 2 3 4 5 6 7 8 9 10Zolmitriptan 25-50    1-30 45 40 45 40 45 40 45 40 Tartaric acid 0-16.670-10 0-15 0-13.33 0-15 0-13.33 0-15 0-13.33 0-15 0-13.33 Citric acid0-16.67 0-10 0-15 0-13.33 0-15 0-13.33 0-15 0-13.33 0-15 0-13.33Succinic acid 0-16.67 0-10 0-15 0-13.33 0-15 0-13.33 0-15 0-13.33 0-150-13.33 Malic acid 0-16.67 0-10 0-15 0-13.33 0-15 0-13.33 0-15 0-13.330-15 0-13.33 Maleic acid 0-16.67 0-10 0-15 0-13.33 0-15 0-13.33 0-150-13.33 0-15 0-13.33 Ascorbic acid 0-5    0-5  0-5  0-5    0-5  0-5   0-5  0-5    0-5  0-5    Lactic acid 0-10   0-10 0-10 0-10   0-10 0-10  0-10 0-10   0-10 0-10   Surfactants (e.g. 0-0.2  0 0 0 0.2 0.2 0 0 0 0polysorbate 20, polysorbate 80) EDTA 0-0.01  0 0 0 0 0 0.01 0.01 0 0(Antioxidant Chelator) Methionine 0-1    0 0 0 0 0 0 0 1 1 (Antioxidant)Deionized water qs qs qs qs qs qs qs qs qs qs 100% 100% 100% 100% 100%100% 100% 100% 100% 100% *Ingredients are expressed in % w/w

The present disclosure contemplates that sumatriptan or other triptanmay be substituted for zolmitriptan in similar amounts or proportions asdescribed above.

The liquid coating formulations according to the present disclosuregenerally exhibit the ability to consistently coat the microneedles withadequate content and morphology, and result in a stable solid-state(dried) formulation, containing less than 5% water, preferably less than3%. The liquid formulations are applied to the microneedle arrays andthe microprojection tips thereof using an engineered coater which allowsaccurate control of the depth of the microprojection tips dipping intothe liquid film. Examples of suitable coating techniques are describedin U.S. Pat. No. 6,855,372, included herein by reference in itsentirety. Accordingly, the viscosity of the liquid plays a role inmicroprojection member coating process as has been described. See Ameri,M.; Fan, S C.; Maa, Y F (2010); “Parathyroid hormone PTH(1-34)formulation that enables uniform coating on a novel transdermalmicroprojection delivery system;” Pharmaceutical Research, 27, pp.303-313; see also Ameri M, Wang X, Maa Y F (2010); “Effect ofirradiation on parathyroid hormone PTH(1-34) coated on a noveltransdermal microprojection delivery system to produce a sterileproduct—adhesive compatibility;” Journal of Pharmaceutical Sciences, 99,2123-34.

The coating formulations comprising zolmitriptan have a viscosity lessthan approximately 500 centipoise (cP) and greater than 3 cP, or lessthan approximately 400 cP and greater than 10 cP, or less thanapproximately 300 cP and greater than 50 cP, or less than 250 cP andgreater than approximately 100 cP. In some embodiments, the viscosity ofthe liquid formulation prior to coating is at least 20 cP. In otherembodiments, the viscosity is about 25 cP, or about 30 cP, or about 35cP, or about 40 cP, or about 45 cP, or about 50 cP, or about 55 cP, orabout 60 cP, or about 65 cP, or about 70 cP, or about 75 cP, or about 80cP, or about 85 cP, or about 90 cP, or about 95 cP, or about 100 cP, orabout 150 cP, or about 200 cP, or about 300 cP, or about 400 cP, orabout 500 cP. In other embodiments, the viscosity is more than about 25cP, or a more than about 30 cP, or more than about 35 cP, or more thanabout 40 cP, or more than about 45 cP, or more than about 50 cP, or morethan about 55 cP, or more than about 60 cP, or more than about 65 cP, ormore than about 70 cP, or more than about 75 cP, or more than about 80cP, or more than about 85 cP, or more than about 90 cP, or more thanabout 95 cP, or more than about 100 cP, or more than about 150 cP, ormore than about 200 cP, or more than about 300 cP, or more than about400 cP, or less than about 500 cP. In a preferred embodiment, theviscosity of the coating formulation is more than about 80 cP and lessthan about 350 cP; in another preferred embodiment, the viscosity ismore than about 100 cP and less than about 350 cP; and, in anotherpreferred embodiment, the viscosity is more than about 100 cP and lessthan about 250 cP.

Once applied to the microprojections, the coating formulation may havean average thickness of about 10 to about 400 microns, or from about 30to about 300 microns, or from about 100 microns to about 175 microns, orfrom about 115 to about 150 microns, or about 135 microns, as measuredfrom the microprojection surface. Although it is preferable that thecoating formulation have a uniform thickness covering themicroprojection, the formulation may vary slightly as a result of themanufacturing process. As shown in FIG. 31, the microprojections aregenerally coated uniformly because they penetrate the stratum corneum.In some embodiments, the microprojections are not coated the entiredistance from the tip to the base; instead, the coating covers a portionof the length of the microprojection, measured from tip to the base, ofat least about 10% to about 80%, or 20% to about 70%, or about 30% toabout 60%, or about 40% to about 50% of the length of themicroprojection.

The liquid coating formulation is applied to an array ofmicroprojections so as to deliver a dose of the active agent in theamount of about 0.1 mg to 10 mg per array. In the case of zolmitriptan,the dose is about 0.25 mg to about 10 mg, or about 1 mg or more, orabout 1.9 mg or more, or about 2 mg or more, or about 3 mg or more, orabout 3.8 mg or more, or about 4 mg or more, or about 5 mg or moredelivered to the stratum corneum per array (via a patch or other form).In one embodiment, the amount of the zolmitriptan contained in coatingformulation is 1-1000 μg or 10-100 μg. In one embodiment, the array sizeis about 5.5 cm² comprising a dose of about 3.8 mg zolmitriptan, or thearray size is about 3 cm² comprising a dose of about 3.8 mg, or thearray size is about 3 cm², comprising a dose of about 1.9 mg. The amountof zolmitriptan or similar active agent per microprojection could rangefrom about 0.001 to about 1000 μg, or about 0.01 to about 100 μg, orabout 0.1 to about 10 μg, or about 0.5 to about 2 μg. In one embodiment,the amount of zolmitriptan or similar active agent per microprojectionis about 1 μg. The microprojection shape and size has a significantbearing on the drug loading capacity and on the effectiveness of drugdelivery.

Importantly, the formulations of the present disclosure do not primarilyrely on penetration enhancers to facilitate absorption of the activeagent into the bloodstream. Penetration enhancers, such as Azone® andfatty acids, often cause skin irritation and have other disadvantages.Thus, the systems of the present disclosure are either completely freeof a penetration enhancer, or are substantially free thereof. In otherembodiments, there is less than 15% w/w of penetration enhancer present,or less than 10% w/w, or less than 5% w/w, or less than 2.5% w/w, orless than 1% w/w present in the dried formulation.

The biologically active agent formulations are generally prepared as asolid coating by drying a coating formulation on the microprojection, asdescribed in U.S. Application Pub. No. 2002/0128599. The coatingformulation is usually an aqueous formulation. During a drying process,all volatiles, including water are mostly removed; however, the finalsolid coating may still contain about 1% w/w water, or about 2% w/wwater, or about 3% w/w water, or about 4% w/w water, or about 5% w/wwater. The oxygen and/or water content present in the formulations arereduced by the use of a dry inert atmosphere and/or a partial vacuum. Ina solid coating on a microprojection array, the drug may be present inan amount of less than about 10 mg per unit dose or less than about 4 mgor less than about 3 mg or less than about 2 mg or less than about 1 mg.With the addition of excipients, the total mass of solid coating may beless than about 15 mg per unit dose.

The microprotrusion member is usually present on an adhesive backing,which is attached to a disposable polymeric retainer ring. This assemblyis packaged individually in a pouch or a polymeric housing. In additionto the assembly, this package contains a dead volume that represents avolume of at least 3 mL. This large volume (as compared to that of thecoating) acts as a partial sink for water. For example, at 20° C., theamount of water present in a 3 mL atmosphere as a result of its vaporpressure would be about 0.05 mg at saturation, which is typically theamount of residual water that is present in the solid coating afterdrying. Therefore, storage in a dry inert atmosphere and/or a partialvacuum will further reduce the water content of the coating resulting inimproved stability.

According to the disclosure, the coating can be applied to themicroprojections by a variety of known methods. For example, the coatingmay be only applied to those portions of the microprojection member ormicroprojections that pierce the skin (e.g., tips). The coating is thendried to form a solid coating. One such coating method comprisesdip-coating. Dip-coating can be described as a method to coat themicroprojections by partially or totally immersing the microprojectionsinto a coating solution. By use of a partial immersion technique, it ispossible to limit the coating to only the tips of the microprojections.

A further coating method comprises roller coating, which employs aroller coating mechanism that similarly limits the coating to the tipsof the microprojections. The roller coating method is disclosed in U.S.Application Pub. No. 2002/0132054. As discussed in detail therein, thedisclosed roller coating method provides a smooth coating that is noteasily dislodged from the microprojections during skin piercing.

A further coating method that can be employed within the scope of thepresent invention comprises spray coating. Spray coating can encompassformation of an aerosol suspension of the coating composition. In oneembodiment, an aerosol suspension having a droplet size of about 10 to200 picoliters is sprayed onto the microprojections and then dried.

Pattern coating can also be employed to coat the microprojections. Thepattern coating can be applied using a dispensing system for positioningthe deposited liquid onto the microprojection surface. The quantity ofthe deposited liquid is preferably in the range of 0.1 to 20nanoliters/microprojection. Examples of suitable precision-meteredliquid dispensers are disclosed in U.S. Pat. Nos. 5,916,524; 5,743,960;5,741,554; and 5,738,728; which are fully incorporated by referenceherein.

Microprojection coating formulations or solutions can also be appliedusing ink jet technology using known solenoid valve dispensers, optionalfluid motive means and positioning means which is generally controlledby use of an electric field. Other liquid dispensing technology from theprinting industry or similar liquid dispensing technology known in theart can be used for applying the pattern coating of this invention.

In one embodiment of the disclosure, the thickness of the dried coatingformulations comprising zolmitriptan range from about 10 to 100 micronsas measured from the microprojection surface, or from about 20 to 80microns, or from about 30 to 60 microns, or from about 40 to 50 microns.The desired coating thickness is dependent upon several factors,including the required dose and, hence, coating thickness necessary todeliver the dose, the density of the microprojections per unit area ofthe sheet, the viscosity, the solubility and concentration of thecoating composition and the coating method chosen. The thickness ofcoating applied to microprojections can also be adapted to optimizestability of the zolmitriptan. Known formulation adjuvants can also beadded to the coating formulations provided they do not adversely affectthe necessary solubility and viscosity characteristics of the coatingformulation nor the physical integrity of the dried coating.

The coating is applied to the microneedles, which protrude from thebase, or streets, of the microneedle array. The coating is applied tothe tips of the microneedles, and is not intended to cover themicroneedles and the surface of the microneedle array. This reduces theamount of drug per transdermal patch, which is advantageous in light ofFDA Guidance on the danger of residual drug on transdermal deliverysystems, which suggests that the amount of residual drug in a systemshould be minimized. See FDA Guidance for Industry, Residual Drug inTransdermal and Related Drug Delivery Systems (August 2011). Applicant'sstrategy was to maximize drug release into skin per unit area, withoutusing an excess of drug for coating.

After a coating has been applied, the coating formulation is dried ontothe microprojections by various means. The coated microprojection membermay be dried in ambient room conditions. However, various temperaturesand humidity levels can be used to dry the coating formulation onto themicroprojections. Additionally, the coated member can be heated, storedunder vacuum or over desiccant, lyophilized, freeze dried or similartechniques used to remove the residual water from the coating.

Coating was conducted at ambient temperature utilizing a roller drum,rotating at 50 rpm, in a drug formulation reservoir (2 mL in volume) toproduce a film of controlled thickness of around 270 μm in thickness.Further information about the coating process can be found in U.S. Pat.No. 6,855,372, incorporated herein in its entirety by reference.Microprojection arrays are dipped into the drug film, and the amount ofcoating is controlled by the number of dips (passes) through the drugfilm.

During the drying process, there may be issues related to forming auniform coating the microprojection with a controlled and consistentthickness. One common issue in transdermal patch coating, called“dripping” or “teardrop” formations, occurs when the coating is dryingand the coating accumulates at the end of the microprojections in a“teardrop” shape. This teardrop shape can blunt the sharp end of themicroneedle, potentially impacting the effectiveness and uniformity ofpenetration. Uneven layers of formulation on the microprojectionsresults in uneven, and sometimes inadequate drug delivery. Additionally,the issues in the drying process cause issues of quality control informulation coating. Preferred liquid coating formulations comprisezolmitriptan in an amount of 30% w/w to about 60% w/w, preferably about40% w/w to about 50% w/w, more preferably about 45% w/w, and tartaricacid in an amount of about 5% w/w to about 25% w/w, preferably about 10%w/w to about 20% w/w, more preferably about 15% w/w, in a liquidcarrier, preferably water, more preferably deionized water. With theseliquid coating formulations, Applicant surprisingly found thatmaintaining a viscosity of about 150 cP to about 350 cP, preferablyabout 200 cP to about 300 cP, more preferably about 250 centipoise, anda surface tension of about 50 mNm⁻¹ to about 72 mNm⁻¹, preferably about55 mNm⁻¹ to about 65 mNm⁻¹, more preferably about 62.5 mNm⁻¹ wasrequired to avoid dripping. Teardrop formation could be avoided whilesimultaneously allowing each dip of microprojections into the liquidcoating formulation to pick up sufficient volume of liquid coatingformulation, thereby achieving the desired drug dose with a minimumnumber of dips. When the viscosity and surface tension of the coatingsolution are high enough, the coated liquid does not quickly drip backor form a teardrop shape after dipping and before drying.

The products and methods described herein with respect to delivery ofzolmitriptan in a method of rapidly achieving therapeutic concentrationsof zolmitriptan for treatment of migraine or cluster headache also canbe applied to other triptans, including sumatriptan, rizatriptan,naratriptan, eletriptan, almotriptan, frovatriptan, avitriptan, anddonitriptan.

In one aspect, the route of administration of zolmitriptan isintramuscularly, intracutaneously, subcutaneously, intranasally, oralinhalation, transdermally, buccally, pulmonary, or sublingually. Forexample, a formulation designed for intramuscular or subcutaneousdelivery would contain 1 mg of zolmitriptan (base) and 0.3 mg oftartaric acid in 1 mL of 0.9% w/v saline. Further, a formulationdesigned for pulmonary delivery would be in the form of zolmitriptansalt dissolved or suspended in water or a zolmitriptan powder generatedusing milling, supercritical fluid process, spray drying or spray freezedrying for inhalation delivery and would produce respirable particleswith a controlled particle size of about 0.5-5.8 μm mass medianaerodynamic diameter (MMAD) to ensure that a significant fraction ofzolmitriptan would be deposited in the lung. The processes to producezolmitriptan powder can be used directly by metering in from a powderreservoir or premetering into a dry powder inhaler (DPI) format, or theparticulates may be suspended/dispersed directly into a suspendingmedia, such as a pharmaceutically acceptable propellant e.g.,hydrofluoralkanes (selected from the group consisting of:1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and amixture of 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture of thereof), in ametered dose inhaler (MDI) format. The particles produced may becrystalline or may be amorphous depending on the process to generate thezolmitriptan powder. In one aspect, the zolmitriptan dose ranges from0.5 to 4 mg, administered at the onset of migraine or cluster headache.

V. PACKAGING, STERILIZATION

Improved physical stability of the dry coated formulations provides notonly the benefit of an increased storage or shelf life for thetherapeutic agent itself, but enhances efficacy in that once stabilizedin accordance with the compositions of and methods for formulating anddelivering of the present invention, the therapeutic agents becomeuseful in a greater range of possible formulations, and with a greatervariety of therapeutic agent delivery means.

The present disclosure comprises an active agent formulation wherein thedeterioration by oxygen and/or water is minimized and/or controlled bythe manufacture and/or packaging of the active agent formulation in adry inert atmosphere. The formulation may be contained in a dry inertatmosphere in the presence of a desiccant, optionally in a chamber orpackage comprising a foil layer.

The desiccant can be any known to those skilled in the art. Some commondesiccants include, but are not limited to molecular sieve, calciumoxide, clay desiccant, calcium sulfate, and silica gel. The desiccantmay be one that can be placed with the biologically activeagent-containing formulation in the presence of an inert atmosphere in apackage comprising a foil layer.

In another aspect, the active agent formulation is packaged in a chambercomprising a foil layer after the formulation is coated onto themicroprojection array delivery device. In this embodiment, a desiccantis contained in the chamber, preferably attached to a chamber lid whichcomprises a foil layer, and the chamber is purged with dry nitrogen orother inert gas such as a noble gas prior to the deliverydevice-containing foil chamber being sealed by the foil lid. Anysuitable inert gas can be used herein to create the dry inertatmosphere.

In one embodiment, the compositions of and methods for formulating anddelivering zolmitriptan suitable for intracutaneous delivery utilize apatch assembly. This patch assembly is manufactured and/or packaged in adry inert atmosphere, and in the presence of a desiccant. In oneembodiment, the patch assembly is manufactured in a dry inert atmosphereand/or packaged in a chamber comprising a foil layer and having a dryinert atmosphere and a desiccant. In one embodiment, the patch assemblyis manufactured and/or packaged in a partial vacuum. In one embodiment,the patch assembly is manufactured and/or packaged in a dry inertatmosphere, and a partial vacuum. In one embodiment, patch assembly ismanufactured in a dry inert atmosphere under a partial vacuum and/orpackaged in a chamber comprising a foil layer and having a dry inertatmosphere, a partial vacuum, and a desiccant.

Generally, in the noted embodiments of the present invention, the inertatmosphere should have essentially zero water content. For example,nitrogen gas of essentially zero water content (dry nitrogen gas) can beprepared by electrically controlled boiling of liquid nitrogen. Purgesystems can be also used to reduce moisture or oxygen content. A rangefor a partial vacuum is from about 0.01 to about 0.3 atmospheres.

In an aspect of this embodiment, the zolmitriptan further comprises abiocompatible carrier. In another embodiment, there is an intracutaneousdelivery system, adapted to deliver zolmitriptan, comprising: (a) amicroprojection member including a plurality of microprojections thatare adapted to pierce the stratum corneum of a patient; (b) a hydrogelformulation comprised of zolmitriptan, wherein the hydrogel formulationis in communication with the microprojection member; and (c) packagingpurged with an inert gas and adapted to control environmental conditionssealed around the microprojection member, wherein the sealed package hasbeen exposed to radiation to sterilize the microprojection member.

In another embodiment, there is an intracutaneous delivery system,adapted to deliver zolmitriptan, comprising: (a) a microprojectionmember including a plurality of microprojections that are adapted topierce the stratum corneum of a patient; (b) a solid film disposedproximate the microprojection member, wherein the solid film is made bycasting a liquid formulation comprising zolmitriptan, a polymericmaterial, a plasticizing agent, a surfactant and a volatile solvent; and(c) packaging purged with an inert gas and adapted to controlenvironmental conditions sealed around the microprojection member,wherein the sealed package has been exposed to radiation to sterilizethe microprojection member.

The present disclosure is also to a method for terminally sterilizing apatch assembly adapted to deliver zolmitriptan, comprising the steps of:(a) providing a microprojection member having a plurality ofmicroprojections that are adapted to pierce the stratum corneum of apatient having a biocompatible coating comprising zolmitriptan disposedon the microprojection member; and (b) exposing the microprojectionmember to radiation selected from the group consisting of gammaradiation and e-beam, wherein the radiation is sufficient to reach adesired sterility assurance level. Such sterility assurance level may be10⁻⁶ or 10⁻⁵. The method may further comprise sealing themicroprojection member with a desiccant inside packaging purged with aninert gas and exposing the packaged microprojection member to radiationselected from the group consisting of gamma radiation and e-beamradiation, wherein the radiation is sufficient to reach a desiredsterility assurance level.

In an aspect of this embodiment, the method further comprises the stepof mounting a patch comprised of a microprojection member attached to anadhesive backing on a pre-dried retainer ring to form a patch assembly,and subsequently sealing the microprojection member inside thepackaging. In an aspect of this embodiment, the system further comprisesa desiccant sealed inside the packaging with the patch assembly, and/orthe packaging is purged with nitrogen, and/or the packaging comprises apouch comprised of a foil layer. Preferably, the foil layer comprisesaluminum.

The step of exposing the microprojection member to radiation may occurat approximately −78.5 to 25° C., or the member may be exposed toradiation at ambient temperature. The radiation may be in the range ofapproximately 5 to 50 kGy, or approximately 10 to 30 kGy, orapproximately 15 to 25 kGy, or approximately 21 kGy, or approximately 7kGy. In one aspect of this embodiment, the radiation is delivered to themicroprojection member at a rate of at least approximately 3.0 kGy/hr.

As described herein, Applicant developed a zolmitriptan formulationwhich, when coated on the microneedle members of the present disclosure,is stable and maintains its amorphous character for at least 6 months,or at least 9 months, or at least 12 months, or at least 18 months, orat least 24 months after being exposed to radiation as described above.

In one embodiment, the dried zolmitriptan formulation on themicroneedles retains for at least 6 months approximately 100% of initialpurity, or approximately 99% of initial purity, or approximately 98% ofinitial purity, or approximately 97% of initial purity, or approximately96% of initial purity, or approximately 95% of initial purity, orapproximately 90% of initial purity. In other aspects, such purity isretained for at least 9 months, or at least 12 months, or at least 18months, or at least 24 months after packaging. In a further embodiment,the zolmitriptan coating on the microneedles retains its purity asdescribed in this paragraph, and also substantially maintains itsamorphous character for at least 6 months, or at least 9 months or atleast 12 months, or at least 18 months, or at least 24 months afterpackaging.

In one embodiment, a method for manufacturing a patch assembly for anintracutaneous delivery system adapted to deliver a zolmitriptan,comprises the steps of: providing a microneedle member having aplurality of microneedles that are adapted to penetrate or pierce thestratum corneum of a patient having a biocompatible coating disposed onthe microneedle member, the coating being formed from a coatingformulation having zolmitriptan and disposed thereon; sealing themicroneedle member with a desiccant inside packaging purged withnitrogen and adapted to control environmental conditions surrounding themicroneedle and exposing the microneedle member to radiation selectedfrom the group consisting of gamma radiation, e-beam and x-ray whereinthe radiation is sufficient to reach a desired sterility assurancelevel.

In accordance with another embodiment of the invention, a method fordelivering stable biologically active agent formulations comprises thefollowing steps: (i) providing a microprojection member having aplurality of microprojections, (ii) providing a stabilized formulationof biologically active agent; (iii) forming a biocompatible coatingformulation that includes the formulation of stabilized biologicallyactive agent, (iv) coating the microprojection member with thebiocompatible coating formulation to form a biocompatible coating; (v)stabilizing the biocompatible coating by drying; and (vi) applying thecoated microprojection member to the skin of a subject.

Additionally, optimal stability and shelf life of the agent is attainedby a biocompatible coating that is solid and substantially dry. However,the kinetics of the coating dissolution and agent release can varyappreciably depending upon a number of factors. It will be appreciatedthat in addition to being storage stable, the biocompatible coatingshould permit desired release of the therapeutic agent.

Encompassed herein is a method for terminally sterilizing a transdermaldevice adapted to deliver a zolmitriptan, comprising the steps of:providing a microprojection member having a plurality ofmicroprojections that are adapted to penetrate or pierce the stratumcorneum of a patient having a biocompatible coating disposed on themicroprojection member, the coating being formed from a coatingformulation having at least one triptan, preferably zolmitriptan,disposed thereon; and exposing the microprojection member to radiationselected from the group consisting of gamma radiation and e-beam,wherein the radiation is sufficient to reach a desired sterilityassurance level. A further aspect of this method comprises the furtherstep of sealing the microprojection member inside packaging adapted tocontrol environmental conditions surrounding the microprojection member.In one aspect the packaging comprises a foil pouch. A further aspect ofthis method, comprises the further step of sealing a desiccant insidethe packaging. Further, the method comprises the step of mounting themicroprojection member on a pre-dried retainer ring prior to sealing themicroprojection member inside the packaging. A further aspect of thismethod comprises the step of purging the packaging with an inert gasprior to sealing the packaging. In one embodiment, the inert gascomprises nitrogen.

VI. IN VIVO PHARMACOKINETICS (PK)

The intracutaneous/transdermal systems of the present invention provideserum concentrations to the bloodstream faster and with less overalldrug exposure as compared to oral doses of the same drug. For example,the absorption of intracutaneously administered zolmitriptan deliveredvia the systems of the present disclosure results in a C_(max) of lessthan 50 mg/mL and the T_(max) is between about 2 minutes and 30 minutes.In another embodiment, the plasma zolmitriptan AUC for the first 2 hoursis greater than that seen following oral administration, but the plasmazolmitriptan AUC_((0-24 hr)) is less than that seen after oraladministration.

In another aspect, the absorption of the zolmitriptan results in anincrease in the maximum plasma zolmitriptan, but the N-desmethylzolmitriptan production (AUC_(0-24 hr)) is reduced and thus has a lowerlikelihood for metabolite accumulation. The intracutaneousadministration of triptans, including zolmitriptan, avoids the firstpass metabolism in the liver found with oral administration, resultingin higher bioavailability. In particular, metabolism is significantlyreduced resulting in at least about 20% less serum concentration ofN-desmethyl zolmitriptan at time points (e.g., 1.5 hours, 2 hours, 5hours, 10 hours) post-application than seen in oral products. Further,zolmitriptan plasma levels may be increased, but the N-desmethylzolmitriptan production is reduced relative to that produced upon oraladministration of a comparable dose of zolmitriptan. Therefore, there isa lower likelihood for metabolite accumulation. However, becauseN-desmethyl zolmitriptan is more active at the target sites thanzolmitriptan, the present invention is surprisingly effective attreating migraine or cluster headache as detailed below. In addition,the apparent half-life of zolmitriptan is reduced compared to oraladministration, such that the duration of side effects may be reduced.

In another aspect, the plasma concentration of N-desmethyl zolmitriptanis about 0.05 to 0.9 ng/ml after about 15 minutes after application, orabout 0.1 to 1.4 ng/ml after about 30 minutes, or about 0.1 to 1.6 ng/mlafter about 1 hour, or about 0.1 to 1.4 ng/ml after about 1.5 hours, orabout 0.1 to 1.3 ng/ml after about 2 hours, or less than about 0.7 ng/mlafter 5 hours, or less than about 0.2 ng/ml after 10 hours.

Further, the intracutaneously delivered biocompatible coating comprisesa dose of the zolmitriptan in the range of approximately 0.2 to 10 mg,preferably 1 to 5 mg, more preferably approximately 1.9 or 3.8 mg,wherein intracutaneous delivery of the zolmitriptan results in a plasmaC_(max) of at least 2 ng/mL zolmitriptan, at least 3.6 ng/mLzolmitriptan, at least 4 ng/mL zolmitriptan, at least 6 ng/mLzolmitriptan, at least 9 ng/mL zolmitriptan, at least 10 ng/mLzolmitriptan, at least 12 ng/mL zolmitriptan, at least 14 ng/mLzolmitriptan, at least 16 ng/mL zolmitriptan, at least 18 ng/mLzolmitriptan, at least 20 ng/mL zolmitriptan, at least 25 ng/mLzolmitriptan, at least 30 ng/mL zolmitriptan, at least 40 ng/mLzolmitriptan, at least 45 ng/mL zolmitriptan, at least 50 ng/mLzolmitriptan, less than 50 ng/mL zolmitriptan, at least 55 ng/mLzolmitriptan, at least 60 ng/mL zolmitriptan or at least 65 ng/mLzolmitriptan after one application or two applications.

Also, the intracutaneous delivery of the zolmitriptan results in aplasma T_(max) of no more than 1 minute, no more than 2 minutes, no morethan 3 minutes, no more than 4 minutes, no more than 5 minutes, no morethan 8 minutes, no more than 10 minutes, no more than 12 minutes, nomore than 15 minutes, no more than 20 minutes, no more than 30 minutes,no more than 35 minutes, no more than 40 minutes, no more than 45minutes, no more than 50 minutes, no more than 55 minutes, is between 2minutes and 30 minutes, or is no more than 60 minutes after oneapplication.

In one embodiment, the T_(max) of intracutaneously administeredzolmitriptan via the inventive systems occurs about 2 hours or morebefore conventional release oral zolmitriptan tablets, or about 1.8hours or more before such tablets, or about 1.6 hours or more beforesuch tablets, or about 1.4 hours or more before such tablets, or about1.2 hours or more before such tablets, or about 1.0 hours or more beforesuch tablets, or about 0.8 hours or more before such tablets, or about0.6 hours or more before such tablets, or about 0.4 hours or more beforesuch tablets, or about 0.2 hours or more before such tablets.

In another embodiment, the T_(max) of intracutaneously administeredzolmitriptan via the inventive systems occurs about 3 hours or morebefore ZOMIG® (zolmitriptan) orally disintegrating tablets, or about 2.5hours or more before such tablets, or about 2.0 hours or more beforesuch tablets, or about 1.5 hours or more before such tablets, or about1.0 hours or more before such tablets, or about 0.5 hour before suchtablets.

In further embodiments, the T_(max) of intracutaneously administeredzolmitriptan via the inventive systems occurs about 3 hours or morebefore zolmitriptan nasal spray, or about 2.5 hours or more before suchspray, or about 2.0 hours or more before such spray, or about 1.5 hoursor more before such spray, or about 1.0 hour or more before such spray,or about 0.5 hour or more before such spray.

In another embodiment, the elimination rate (t_(1/2)) forintracutaneously administered zolmitriptan via the inventive systems isabout 0.75 hour, or 1.0 hour, or 1.1 hour, or 1.2 hour, or 1.3 hour, or1.4 hour, or 1.5 hour, or 1.6 hour, or 1.7 hour, or 1.8 hour, or 1.9hour, or 2.0 hours. Such elimination rate (t_(1/2)) is approximatelythree times the rate of zolmitriptan conventional tablets, orapproximately twice the rate of zolmitriptan conventional tablets.

In further embodiments, the C_(max) for intracutaneously administeredzolmitriptan via the inventive systems is about 1 to about 8 timeshigher than the C_(max) of conventional oral 2.5 mg zolmitriptantablets, or about 1.5 to about 7 times higher, or about 2 to about 6times higher, or about 3 to about 5 times higher, or about 4 timeshigher.

Further, the mean peak exposure (C_(max)) is about 2 to about 5 timeshigher for intracutaneous zolmitriptan relative to the oral tablets. Ina further aspect, the mean peak exposure (C_(max)) for theintracutaneous zolmitriptan of the present invention is about 1.0 toabout 40.0 mg/mL, or about 5.0 to about 35.0 mg/mL, or about 10.0 toabout 30.0 mg/mL, or about 15.0 to about 25.0 mg/mL, or about 20.0 toabout 30.0 mg/mL, or about 25 mg/mL.

Additionally, compared to conventional oral zolmitriptan 2.5 mg,intracutaneous zolmitriptan of the invention at doses ranging from about0.5 mg to about 4.0 mg have a bioavailability of about 50% to about 100%of the oral bioavailability. In other embodiments, the bioavailabilityof intracutaneous is about 55% to about 95%, or about 60% to about 90%,or about 65% to about 85%, or about 70% to about 80%, or about 75% ofthe oral bioavailability.

Finally, the present invention encompasses formulations and devices thatare bioequivalent to the M207 Intracutaneous Delivery System describedherein. Thus, the disclosure covers products where bioequivalence isestablished by (i) a 90% Confidence Interval (CI) for AUC which isbetween 0.80 and 1.25; and (ii) a 90% CI for C_(max) which is between0.80 and 1.25.

VII. METHODS OF TREATMENT

The drug-device combinations of the present invention can be used totreat a variety of diseases and conditions, including migraine andcluster headache. In one embodiment of the present invention, there is amethod for treatment or alleviation of migraine or cluster headache toan individual in need thereof, comprising administration of atherapeutically effective amount of a zolmitriptan-based agent, whereinthe absorption of the zolmitriptan-based agent results in a plasmaC_(max) of less than 50 ng/mL. Doses include about 0.2 mg to about 10 mgzolmitriptan. The dose may also be 0.48 mg, 0.96 mg, 1.9 mg, and 3.8 mgzolmitriptan. Doses also include a single patch administration of either1.0 mg, 1.9 mg, or 3.8 mg, or two patches of 1.9 mg. These doses can bedelivered utilizing the patch(es) described herein and can be applied tothe skin of any part of the body. In a preferred embodiment, thezolmitriptan dose(s) is delivered via the patch to the upper arm totreat a single migraine or cluster headache attack.

In certain embodiments, the methods of treatment of migraine or clusterheadache as described herein result in improvement with respect to thefollowing therapeutic endpoints: Migraine Pain freedom at 1 hour, 2hours, or 4 hours after dosing; Cluster headache pain freedom at 15 or30 minutes after dosing, most bothersome other migraine symptom freedomat 1 hour or 2 hours after dosing; freedom from a patient's previouslyidentified most bothersome other cluster headache symptom at 15 or 30minutes after dosing, migraine pain relief at 1 hour, 2 hours or 4hours; Cluster headache pain relief at 15 or 30 minutes after dosing,pain relief at 30 minutes; photophobia freedom at 2 hours; phonophobiafreedom at 2 hours; pain relief at 15 minutes; pain relief at 3 hours;pain relief at 4 hours; nausea freedom at 2 hours; pain freedom at 30minutes; pain freedom at 24 hours; and pain freedom at 48 hours.Further, there is an improvement in terms of treated patients requiringrescue medication. Improvement as to pain, most bothersome othersymptom, photophobia, phonophobia, nausea, and other bothersomesymptoms, is assessed sequentially, in a fixed-sequential testingmethod.

Tables 45-48 demonstrate effectiveness of the claimed invention forreducing or eliminating pain from migraine or cluster headaches, ascompared to triptans and alternative forms of zolmitriptan. Theseresults are based on one embodiment of the claimed invention, but arenot so limited.

Shown in Table 45, methods described herein demonstrate that the oneembodiment of the claimed invention shows significant improvement inpatients being pain free at 1 hour after dosing, as compared to a tabletof zolmitriptan. The results shown in Table 45 are merely one example ofthe significant efficacy that the claimed invention provides over theknown methods for treating migraine or cluster headache withzolmitriptan. In one embodiment of the claimed invention, with azolmitriptan dose of 1 mg, more than 15% of patients were pain free at 1hour after treatment. In another embodiment (1.9 mg), more than 20% ofpatients were pain free at 1 hour. In a third embodiment (3.8 mg), morethan 25% of patients were pain free at 1 hour. This shows improvedefficacy over nasal treatment of zolmitriptan, with which it has beenshown that only about 10% of patients are pain free at 1 hour. Thecurrent invention is also significantly more efficacious than 2.5 mg, 5mg, and 10 mg tablets and 2.5 mg orally dissolving tablets, all of whichonly achieve pain freedom after 1 hour of 10% or less. The claimedinvention also shows significant improvements in pain free results at 2hours and 4 hours after treatment. In one embodiment, at 2 hours aftertreatment, more than thirty percent of patients were pain free. Inanother embodiment, at 2 hours, more than forty percent of patients werepain free. In a third embodiment, at 4 hours after treatment, more thanfifty percent of patients were pain free. These are significantimprovements over nasal treatments using zolmitriptan, in which lessthan twenty five and forty percent of patients are pain free after twoand four hours from treatment, respectively. These results are alsocomparable to other zolmitriptan dosage forms and delivery routes, andat forty percent pain free at two hours better than all otherzolmitriptan dosage forms and delivery routes. These results are alsoshown graphically in FIG. 25.

Table 46 provides a comparison of resulting pain relief between theclaimed invention and the current methods for treating migraine orcluster headaches with zolmitriptan. In the 1 mg, 1.9 mg, and 3.8 mgembodiments, pain relief of over 45%, 55%, and 65% respectively wasachieved at just one hour after dosing. More than 65%, 68%, and 80%respectively experienced pain relief at two hours after dosing. With the3.8 mg embodiment, over 80% of patients experienced pain relief at fourhours after dosing. All three embodiments demonstrated significantimprovements in pain relief at 1 hour when compared to the otherzolmitriptan dosage forms and delivery routes, and the 3.8 mg embodimentwas also superior to the other zolmitriptan dosage forms at 2 and 4hours. These results are also shown graphically in FIG. 26.

Tables 47 and 48 demonstrate the significant improvements of the claimedinventions over other triptans used for treating migraine or clusterheadaches, for eliminating or reducing migraine or cluster headachepain. As shown in Table 47, the claimed invention shows significantimprovements in pain free results over other triptans which arecurrently used in the art. At 17.7%, 20.5%, and 26.8% pain freedom at 1hour for the 1 mg, 1.9 mg, and 3.8 mg embodiments respectively, allthree strengths achieved higher levels of pain freedom than any of theother triptans. At 41.5% and 54.9% pain freedom at 2 and 4 hours, the3.8 mg embodiment was still superior to all of the other triptans. Theseresults are also shown graphically in FIG. 27. As shown in Table 48, theclaimed invention shows significant improvements in pain relief results,over other triptans which are currently used in the art. At 46.8%,55.4%, and 68.3% pain relief at 1 hour for the 1 mg, 1.9 mg, and 3.8 mgembodiments respectively, all three strengths achieved higher levels ofpain relief than any of the other triptans. At 80.5% and 82.9% painrelief at 2 and 4 hours, the 3.8 mg embodiment was still superior to allof the other triptans. These results are also shown graphically in FIG.28. In another aspect, the plasma T_(max) of the administeredzolmitriptan based agent is between about 2 minutes and 30 minutes. Inone embodiment, administration of the zolmitriptan based agent is bytransdermal or intracutaneous administration. Alternatively, the routeof administration of a zolmitriptan based agent is intravenously,subcutaneously, orally, intranasally, oral inhalation, intracutaneously,transdermally, buccally, or sublingually.

In another embodiment, there is a method for treatment or alleviation ofmigraine or cluster headache in an individual in need thereof,comprising administering a therapeutically effective amount of azolmitriptan based agent, wherein the plasma zolmitriptan AUC for thefirst 2 hours is greater than the plasma zolmitriptan AUC following oraladministration of an equivalent dose of zolmitriptan, but the plasmazolmitriptan AUC_(0-inf) following intracutaneous administration of atherapeutically effective amount of a zolmitriptan based agent is lessthan the plasma zolmitriptan AUC_(0-inf) seen after the oraladministration of an equivalent dose of zolmitriptan. In one aspect ofthis embodiment, administration of the zolmitriptan based agent istransdermal or intracutaneous administration. In one aspect of thisembodiment, the route of administration of a zolmitriptan based agent isintravenously, subcutaneously, orally, intranasally, oral inhalation,intracutaneously, transdermally, buccally, or sublingually.

In another embodiment, there is a method for treatment or alleviation ofmigraine or cluster headache in an individual in need thereof, of atherapeutically effective amount of a zolmitriptan based agent, wherein,in comparison to oral administration of an equivalent dose ofzolmitriptan, the zolmitriptan plasma levels are increased, but theN-desmethyl zolmitriptan production is reduced, thereby reducing thelikelihood for metabolite accumulation. In one aspect of thisembodiment, administration of the zolmitriptan based agent istransdermal or intracutaneous administration. In one aspect of thisembodiment, the route of administration of a zolmitriptan based agent isintravenously, intramuscularly, intracutaneously, subcutaneously,orally, intranasally, oral inhalation, transdermally, buccally, orsublingually.

In another embodiment, there is a method for treatment or alleviation ofmigraine or cluster headache in an individual in need thereof,comprising the administration of a therapeutically effective amount of azolmitriptan based agent, wherein, in comparison to oral administrationof an equivalent dose of zolmitriptan, the apparent half-life ofzolmitriptan is reduced, thereby indicating a likelihood of a reducedduration of side effects. In one aspect of this embodiment,administration of the zolmitriptan based agent is transdermal orintracutaneous administration. In one aspect of this embodiment, theroute of administration of a zolmitriptan based agent is intravenously,intramuscularly, intracutaneously, subcutaneously, orally, intranasally,oral inhalation, transdermally, buccally, or sublingually.

In any of the embodiments disclosed herein, the route of administrationof a zolmitriptan based agent is selected from the group consisting ofintravenously, intramuscularly, intracutaneously, subcutaneously,orally, intranasally, oral inhalation, transdermally, buccally, andsublingually.

In an aspect of this embodiment, the intracutaneously administeredzolmitriptan based agent provides a pharmacokinetic profile similar tothe pharmacokinetic profile provided by subcutaneous administration ofan equivalent dose to the intracutaneously administered sumatriptanbased agent.

In one aspect of the method where the zolmitriptan is administered, theadministration of the zolmitriptan is not associated with effects onblood pressure greater than those seen with oral zolmitriptan, despitefaster absorption.

In one embodiment, there is a method for treatment or alleviation ofmigraine or cluster headache in an individual in need thereof,comprising administration of a therapeutically effective amount of azolmitriptan based agent, wherein the time to achieve maximum plasmaconcentration (T_(max)) was comparable to or less than the T_(max) of anequivalent oral dose of zolmitriptan. In one aspect of this embodiment,administration of the zolmitriptan based agent is transdermal orintracutaneous administration. In one aspect of this embodiment, theroute of administration of a zolmitriptan based agent is intravenously,subcutaneously, orally, intranasally, oral inhalation, intracutaneously,transdermally, buccally, or sublingually. In one aspect of theseembodiments, the generation of N-desmethyl zolmitriptan is reducedrelative to the generation of N-desmethyl zolmitriptan resulting from anoral dose of an equivalent amount of the zolmitriptan based agent. Inanother aspect of these embodiments, the absorption of theintracutaneously administered zolmitriptan based agent results in aC_(max) of less than 50 ng/mL.

VIII. EXAMPLES

The following examples are included to demonstrate certain embodimentsof the invention. Those of skill in the art should, however, in light ofthe present disclosure, appreciate that modifications can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention. Therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

In the examples below, unless stated otherwise, the microprojectionarrays were fabricated by a photo/chemical etching and formed using acontrolled manufacturing process. The method is substantially similar tothat described in M. Cormier et al., “Device for enhancing transdermalagent delivery or sampling,” EP0914178B1, incorporated herein byreference in its entirety. Drug formulation coating on themicroprojection array was conducted at ambient temperature utilizing aroller drum, rotating at 50 rpm, in a drug formulation reservoir (2 mLin volume) to produce a drug coating formulation film of controlledthickness. The method is substantially similar to that described in J.C. Trautman et al., “Method and apparatus for coating skin piercingmicroprojections,” U.S. Pat. No. 6,855,372; J. C. Trautman et al.,“Method and apparatus for coating skin piercing microprojections,” U.S.Pat. No. 7,435,299, incorporated herein by reference in their entirety.Microprojections are dipped into the film. The amount of coating iscontrolled by the number of dips (passes) through the drug film as wellas the drug coating formulation properties. The time between each dipwas a few seconds which was sufficient to dry the coated liquidformulation under ambient conditions. The reservoir was circulated withcoolant to maintain a film temperature of 1° C. Since the reservoir isopen to the ambient air, the coating apparatus was positioned inside adew-point control system. Dew point control minimizes moisturecondensation into or evaporation from the liquid formulation duringcoating. The zolmitriptan-coated microneedle arrays were assembled withadhesive backing to form a patch, and mounted on a retainer ring to forma patch assembly. The patch assembly was packaged in an aluminum pouch(Mangar, New Britain, Pa., USA), purged with dry nitrogen andheat-sealed with a Multivac heat sealer (model C400) (Multivac, KansasCity, Mo., USA).

Example 1—Zolmitriptan Coating Formulations, Characterization, PhysicalProperties

Zolmitriptan is a weak base with a pKa of 9.6. Solubility measurementswere conducted by adding excess zolmitriptan base to 0.5 ml of 0.1 Macid and rotating the suspension overnight at 2-8° C. The suspension wasthen centrifuged. The supernatant was then collected and subsequentlythe concentration of zolmitriptan dissolved was determined. Table 2presents the solubility results of zolmitriptan in the various acids.

TABLE 2 Solubility of Zolmitriptan in Various Acids at 2-8° C. AqueousSolvent Solubility (mg/mL) Citric acid 88.6 Tartaric acid 63.3 Maleicacid 50.5 Succinic acid 59.1 HCl 33.3 De-ionized water 1.3

Zolmitriptan exhibits good solubility in the various acids. It was notedthat the rheological behavior of the zolmitriptan solution was affectedby the counterion in the formulation for pH control. Several weak acidbuffers, including one triacid (citric acid), two diacids (maleic acidand tartaric acid) were tested. The zolmitriptan formulations that wereprepared with citric, maleic and tartaric acids were at pH 5.2, 4.3 and6.2 respectively, at the pKa of the acids. The viscosity profiles offormulations including these acids were measured as a function of time.Citric and maleic acid buffered formulations exhibited rheopecticbehavior, i.e., an increase in viscosity as a function of time, whileformulations buffered by tartaric acid maintained relatively uniformviscosity with time. Given the overall rheological effect, tartaric acidwas selected as the counterion for pH adjustment.

A liquid coating formulation of 33% w/w zolmitriptan, 11% w/w tartaricacid and 56% w/w de-ionized water formulation was prepared at pH 4.5 andcontact angle on titanium substrate was determined to be 65.8 degreesindicative of poorly wettable formulation. To improve wettability offormulation on titanium, polysorbate 20 at concentration of 0.2% w/w wasadded to the zolmitriptan formulation. Contact angle decreased to 51.6degrees.

Static contact angle of drug solution formulations on titanium surfacewas determined using a FDS contact angle meter (Model OCA15) employingan optical contact angle method called “Sessile drop”. For staticcontact angle measurement, a photo snapshot is taken once a drop of thesolution (5 μL) is dispensed from the syringe and laid on a cleantitanium foil surface. The angle between the baseline of the drop andthe tangent at the drop boundary is measured on both sides. Completemeasurement was obtained by averaging the two numbers. At least fivereadings were recorded for each sample.

Coating trials with 33% w/w zolmitriptan, 11% w/w tartaric acid, 0.2%w/w polysorbate 20, qs ad deionized water were conducted. Drugformulation coating on the microprojection array was conducted atambient temperature utilizing a roller drum, rotating at 50 rpm, in adrug formulation reservoir (2 mL in volume) to produce a drugformulation film of controlled thickness. Microprojections were dippedinto the drug film. The amount of coating was controlled by the numberof dips (passes) through the drug coating formulation film. The timebetween each dip was only a few seconds which was sufficient to dry thecoated liquid formulation under the ambient conditions. Since thereservoir was open to the ambient air, the coating apparatus waspositioned inside a dew-point control system. The process is designed tomatch the drug film temperature to the air dew point, which preventsevaporation of the coating formulation over the duration of themanufacturing run. However, undulations in the zolmitriptan liquidformulation were noted visually, which is symptomatic of an uneven film.Concentration of zolmitriptan in the liquid formulation was increased upto 51% w/w (tartaric acid in the formulation was 17% w/w and 0.2% w/wpolysorbate 20). Undulations in film were still noted with the highersolids content formulations. Subsequently, the polysorbate 20 wasremoved, and it was noted that the undulations were no longer present.This is a surprising and non-obvious result, because conventionalteachings in pharmaceutics supported the use of surfactants tofacilitate the production of a smooth, uniform coating.

In another coating embodiment, a 33% w/w zolmitriptan, 11% w/w tartaricacid and 56% w/w deionized water formulation caused high incidence ofwicking on the particular microprojection array utilized, whereby thedrug did not adhere to the microprojections. Although the viscosity ofthe formulation was 22 cP, the design of the microprojection (width of120 μm, length 340 μm) and the thick drug film (calculated filmthickness 270 μm) are such that, in each dip into the drug film themicroprojections would pick a volume of liquid that cannot be dried fastenough, which leads to the drug film spreading onto the base of themicroprojections. A higher solids content formulation 40% w/wzolmitriptan, 13.3% w/w tartaric acid and 46.7% w/w de-ionized water(M207), with a viscosity of 85 cP coated the microprojections uniformlyand no wicking was noted. This formulation was utilized for furtherevaluation. Representative batch formulas are provided in Tables 3 and 4for two strengths of microneedle array patches (internal product nameM207), based on the nominal batch size of 45 g (zolmitriptan base).

TABLE 3 Batch Formula for M207 1 mg Component Quantity (mg/patch)Quantity (g/batch) Zolmitriptan 1 45 Tartaric Acid 0.3 15

TABLE 4 Batch Formula for M207 1.9 mg Component Quantity (mg/patch)Quantity (g/batch) Zolmitriptan 1.9 45 Tartaric Acid 0.6 15

Viscoelastic Properties

The 40% w/w zolmitriptan liquid formulation was evaluated forviscoelastic properties. Viscoelastic characterization of a fluid can bea useful tool for predicting the fluid's gelation tendency. H. A.Barnes, J. F. Hutton, and K. Walters, An Introduction to Rheology(Elsevier, New York, 1989). Measurement of viscoelasticity (i.e.,elastic and viscous components) in a viscometer is based on a complex,theoretical model. Briefly subjecting the material to an oscillatorystress or strain, whose value is small enough not to destroy thematerial's structure, produces the output of phase angle. The phaseangle is the ratio between the viscous modulus and the elastic modulus.A phase angle of 0 degrees corresponds to a fully elastic material,following Hooke's law of elasticity, hence suggesting a more rigid, andordered structure. A phase angle of 90 degrees corresponds to a materialwith fully viscous behavior, indicating a less ordered structure whichis less prone to gelation. The 40% w/w zolmitriptan liquid formulationexhibited high phase angle around 83 degrees indicating that theformulation is not susceptible to gelation.

Characterization of Mechanical Properties of ZP-Zolmitriptan Patches byNanoindentation

Mechanical properties of zolmitriptan coating such as hardness andtoughness were evaluated by nanoindentation for M207 1.9 mg patches.Nanoindentation testing was performed on individual microprojectionscoated with zolmitriptan after the microprojections were broken off atthe base of the titanium array. For hardness measurements, the coatedmicroprojections were sampled from the center and two edge locations ofthe array and 10 indentation measurements were made for each of thethree locations. Hardness and reduced elastic modulus were determinedusing a Berkovich indenter by a Nanomechanical Test System,TriboIndenter. Toughness was determined by fracture toughness usingTriboIndenter with a cube corner indenter. Five indents were made foreach patch sample.

TABLE 5 Nanoindentation results for gamma-irradiated M207 1.9 mg(L/N0203154-gamma) avg avg avg Stability avg H H S.D. E_(r) E_(r) S.D.K_(c) K_(c) S.D. Condition (MPa) (MPa) (GPa) (GPa) (kPa*m^(1/2))(kPa*m^(1/2)) T0 380.89 29.27 8.20 0.33 157.02 17.87 T3M- 357.85 6.278.19 0.33 135.76 2.94 25° C./ 60% RH T3M- 329.34 42.84 7.80 0.47 126.643.08 40° C./ 75% RH T6M- 279.89 8.70 9.09 0.89 117.67 12.03 25° C./ 60%RH T12M- 283.61 4.01 7.15 0.05 164.96 9.20 25° C./ 60% RH

Dynamic Vapor Sorption

Water sorption and desorption isotherms of M207 1.9 mg patches weredetermined at 25° C. by DVS Intrinsic (Surface Measurement Systems,Ltd.). Each patch was exposed to a cycle of controlled relative humidity(RH) at incremental steps ascending from 0% to 65% and subsequentlydescending from 65% to 0%. The change in weight was continually measuredby a microbalance with a 0.1 μg resolution. At each RH step the samplewas allowed to reach equilibrium with dm/dt criterion of 0.0004 beforemoving to the next RH step. An uncoated patch was analyzed under thesame conditions to determine background water uptake by the patchcomponents other than the coated drug formulation.

Crystallinity

X-Ray diffraction (XRD) analysis was performed to characterize the solidstate phases of dried zolmitriptan coating on patch for the M207 1.9 mgsystem. Non-irradiated and gamma-irradiated M207 patches were analyzedand compared to an uncoated patch of the same array design. For eachpatch sample to be analyzed, approximately 45-50 microprojections withzolmitriptan coating were broken off at the base of the titanium arrayand analyzed as bulk by XRD. XRD data was collected by a coupled Theta:2-Theta scan on a Bruker D8 Vantec diffractometer equipped with amicro-focus copper x-ray tube with Montel optics monochromator, 0.5 mmcollimator, a Vantec 500 2-D area detector and laser alignment system.XRD pattern of zolmitriptan coated microprojections were compared tothat of uncoated microprojections. All the sharp peaks present inzolmitriptan coated patch samples were matched with those in theuncoated patch sample. Those sharp peaks were identified as titanium(Ti) metal based on the reference XRD data from ICDD/ICSD database,indicating the crystalline phase result from the Ti microprojectionsubstrate. Zolmitriptan coated patches showed a broad, wide peakcentered at about 18° 2-Theta, which is absent in the uncoated patchsample, indicating the drug coating is amorphous material for bothnon-irradiated and gamma-irradiated patches. Percent crystallinity wascalculated with peak profile fitting, the results are summarized inTable 6, and was monitored on stability as described below.

TABLE 6 Phase Identification and Percent Crystallinity for M207 PatchSamples Sample Phases Present % Crystallinity Non-irradiated M207Ti•Titanium Hexagonal, S.G: 100% (Ti) (LN 0203154-NI) P63/mmc (194)Phase Info 0% drug coating [01-089-3725] Amorphous materialGamma-irradiated Ti•Titanium Hexagonal, S.G: 100% (Ti) M207 P63/mmc(194) Phase Info 0% drug coating (LN 0203154-Gamma) [01-089-3725]Amorphous material Uncoated Patch Ti•Titanium Hexagonal, S.G: 100% (Ti)(Array Design: P63/mmc (194) Phase Info MF1663) [01-089-3725]

Mechanical properties of zolmitriptan coating were evaluated as functionof time and storage condition. Mechanical properties such as hardness,which is a measure of a material's resistance to localized plasticdeformation, elastic modulus a measure of material's resistance to beingdeformed elastically when a force is applied to it (measure ofmaterial's stiffness) and fracture toughness, which describes theability of a material containing a crack to resist fracture, wereevaluated. Multiple coated microprojections from different areas ofindividual ZP-Zolmitriptan patches were sampled for testing. Table 5summarizes the results of nanohardness (H), reduced modulus elasticmodulus (E_(r)), and fracture toughness (K_(c)) for gamma irradiatedM207 1.9 mg patches stored at 25° C./60% RH for up to 12 months and at40° C./75% RH for up to 3 months. The stability results suggest adecreasing trend in hardness and fracture toughness, and an increasingtrend in the elastic modulus.

Zolmitriptan Purity and Content Quantitation

Purity of zolmitriptan was determined by the reverse phase highperformance liquid chromatography (RPHPLC) method (TM-601) at wavelengthof 225 nm. Chromatography for the assay was performed using a PhenomenexKinetex EVO C18, (4.6 mm ID×150 mm, 5 μm) maintained at 30° C. Themobile phase involved a gradient elution, with solvent A: AmmoniumDihydrogen Phosphate buffer:MeOH:Acetonitrile, 70:20:10 (v/v), andsolvent B: Ammonium Dihydrogen Phosphate buffer:Acetonitrile, 30:70(v/v), and was pumped at the flow rate of 0.6 mL/min on an HPLC system(Water Alliance 2695) equipped with a binary pump, a thermostattedautosampler, column compartment, and a PDA detector. Data were collectedand analyzed using Empower Pro (Empower 2 software, Waters Corporation).

In Vitro Dissolution

In vitro dissolution of M207 1.9 mg patches were evaluated usingstandard USP Paddle over Disk apparatus (USP apparatus 5) with Distek2100C 6-position dissolution tester. The paddle height was set at 25 mmabove patch and rotated at 50 RPM. An USP vessel was filled withdegassed 500 mL PBS dissolution medium and the temperature wascontrolled at 32° C. A full patch assembly containing the coated patchadhered to the center of an inner ring and then attached to an outerring was inserted along the vessel wall into the vessel with the coatedmicroprojections facing upright. The release of zolmitriptan from thecoated patch was continually monitored via quantitation of zolmitriptanconcentration of the dissolution medium by UV absorbance using PionRainbow 6-Ch Fiber Optic System with 14 cm dip probe and 10 mmpathlength.

M207 patches stored at room temperature and at 40° C./75% relativehumidity for 10 months were evaluated. The results illustrated in FIGS.6(A)-(C) and Table 7 show instantaneous release of zolmitriptan for allthe patches tested with a steep slope reaching concentration plateau ofcomplete dissolution in less than one minute.

TABLE 7 Concentration-Time of Dissolution of Zolmitriptan Time (s)Percent Dissolution (% D) E-beam irradiated and stored 0 0 at RT for 10months 20 60-80 40  90-100 60 100 80 100 100 100 Non-irradiated andstored at 0 0 40° C./75% RH for 10 months 20 0 40 10-40 60  90-100 80100 100 100 E-beam irradiated and stored 0 0 at 40° C./75% RH for 10months 20  5-10 40 10-50 60  50-100 80 100 100 100

Example 2—Ex Vivo Human Skin

The in vitro, Franz, human skin finite dose model is a tool for thestudy of percutaneous absorption of topically applied drugs. The modeluses ex vivo, human torso skin mounted in specially designed diffusioncells allowing the skin to be maintained at a temperature and humiditythat match typical in vivo conditions. A finite dose (for example, 2mg/cm²-10 mg/cm² of a semisolid, or a transdermal delivery system) offormulation is applied to the outer surface of the skin and drugabsorption is measured by monitoring its rate of appearance in thereceptor solution bathing the inner surface of the skin. Data definingtotal absorption, rate of absorption, as well as skin content can bedetermined in this model.

Dosing.

The zolmitriptan patches were applied to the ex-vivo skin with use of anapplicator. Following dosing, the patch and the skin were immediatelymounted onto a Franz Diffusion Cell.

Dermal Receptor Medium.

Normal phosphate buffered saline (pH 7.4±0.1) with 0.008% gentamicinsulfate (PBSg) solution was utilized when the diffusion cells were firstmounted.

Diffusion Cell and Skin Preparation.

Percutaneous absorption was measured using the in vitro, human skin,Franz finite dose technique. Ex vivo, dermatomed, human torso skin,without obvious signs of skin disease or damage was used in this study.The skin was provided to the testing facility as dermatomed,cryopreserved, and sealed in a water-impermeable bag with continuousstorage at ˜−70° C. Prior to use, it was thawed in ˜37° C. water andthen rinsed in distilled, de-ionized water (ddH2O) to remove anyadherent blood or other material from the surface.

Skin from each donor was cut into multiple smaller sections large enoughto fit on nominal 7 cm2 static Franz diffusion cells. The actualthickness of each skin section was measured in triplicate using aDigital Pocket Thickness Gauge (results in Table 2). Each skin sectionwas then mounted onto a diffusion cell.

The dermal receptor compartment was filled to capacity with PBSg. Theepidermal chamber (also known as the chimney or donor compartment) wasleft un-occluded with exposure to the ambient laboratory environment.The cells were then placed within a rack system and attached to a watercirculation system from which the receptor solution was stirredmagnetically at approximately 600 RPM, and its temperature wasmaintained to achieve a skin surface temperature of 32±1° C. (data onfile). Skin was left to equilibrate for a minimum of 1 hour prior to thebarrier integrity test.

One additional skin section per donor was prepared and underwent allstudy activities, but dosed with a placebo patch, to serve as a negativesample control.

Barrier Integrity Test.

To ensure the barrier integrity of each skin section, its desorption ofwater was measured for trans-epidermal water loss (TEWL). A DelfinVapometer probe was activated, placed onto the skin surface, and theTEWL value recorded. Skin mounted in diffusion cells in which TEWL wasless than 25 g/m2/h were considered acceptable. Skin sections that weredetermined to be unacceptable for dosing may have been used as non-dosednegative sample control cells, if needed. After the barrier integritytest was complete, the receptor solution was replaced with thedesignated stock receptor solution of 0.1× PBSg.

Donor Demographics.

The demographics of the skin donors are summarized in table 8.

TABLE 8 Donor Demographics Skin Thickness Integrity Test Donor ID AgeRace Sex (mm) (g/m²/h) NS021715 51 Black Male 0.40 ± 0.08 8.78 ± 0.66SM081016 50 Caucasian Male 0.49 ± 0.16 8.18 ± 2.63 SG100316 50 BlackFemale 0.50 ± 0.21 8.80 ± 0.29

Dose Administration and Sample Collection.

Prior to administration of the patches to the skin sections, a pre-dose(0 hour) sample was collected as the entirety of the receptor solutionvolume was withdrawn with an approximate 5 mL aliquot of the collectedsample saved for subsequent analysis. The receptor solution was replacedwith the designated stock receptor solution of 0.1×PBSg. The chimney wasthen temporarily removed from the Franz diffusion cell to allow fullaccess to the epidermal surface of the skin.

Immediately following patch application, the skin-patch combination andthe donor compartment (chimney) were replaced onto the receptorcompartment of the Franz diffusion cell.

At the scheduled sampling time points (3, 5, 10, 15, 30, 45, 60, 90,120, 150, 180, 210, 240, 270, and 300 minutes), the receptor solutionwas removed in its entirety, refilled with stock receptor solution, andan approximate 5 mL aliquot of the collected sample was saved forsubsequent analysis. For sample analysis, a 5 mL aliquot was lyophilizedusing vacuum centrifugation and reconstituted in 0.25 mL of ddH₂O.

After the last receptor sample was collected, the patch was removed forsubsequent extraction and analysis. The skin surface wash was performedusing two successive refluxing washes of ddH2O. Each wash cycleconsisted of at least 10 refluxes. The two wash volumes from each donorcell were pooled to generate a single surface wash sample for thediffusion cell.

Following the surface wash, the skin was allowed to dry for no less than10 minutes. Subsequently, the skin was tape stripped with up to ten (10)sequential tapes (e.g. 3M Transpore® tape) to remove and collect thestratum corneum. Tape strips were extracted overnight in ddH2O. The skinwas then dismounted from the cell and separated by manual dissectioninto epidermis and dermis for subsequent extraction and analysis. Skinsections were extracted overnight in ddH2O.

Sample Analysis.

Quantification of zolmitriptan in the collected samples was accomplishedusing a validated HPLC method.

Samples were analyzed on a Shimadzu Series LC System. The HPLC UV/Vismethod used a solvent system consisting of a mobile phase gradient using(Solvent A) 0.1% ammonium acetate with 0.1% acetic acid in H2O and(Solvent B) methanol and was run through a Phenomenex Luna C18(2)column, (100×4.6 mm, 3μ) at a flow rate of 0.5 mL/min for the analysisof zolmitriptan. The column was maintained at 40° C.

Mean Flux Results.

Percutaneous absorption of zolmitriptan through ex vivo human torso skinover 300 minutes from a single application (Mean±SE). The mean flux(μg/cm²/hr) is summarized in table 9 and in coordinating FIG. 30. Thisis an across donor summary, showing results of percutaneous absorptionof zolmitriptan through ex vivo human torso skin over 300 minutes from asingle application (Mean, N=3 donors).

TABLE 9 Mean Flux (μg/cm²/hr) Results: Across Donor Summary Time (hr)*ZP-Zolmitriptan 1.9 mg 0.025 385.3 ± 95.9 0.067 849.4 ± 42.1 0.125 730.5± 41.7 0.208 716.5 ± 46.7 0.375 408.9 ± 26.1 0.625 284.8 ± 15.0 0.875187.7 ± 11.8 1.250 107.3 ± 8.3  1.750 63.77 ± 3.70 2.250 41.34 ± 1.002.750 26.22 ± 0.34 3.250 17.14 ± 0.89 3.750 11.70 ± 1.22 4.250  8.333 ±0.751 4.750  6.436 ± 0.819

Total Absorption and Mass Balance Results.

Results of percutaneous absorption of zolmitriptan into and through exvivo human, torso skin over 300 minutes, from a single application issummarized in table 10. Mean±SE as percent of applied dose (%) and totalmass (m).

TABLE 10 Total Absorption and Mass Balance Results across Donor SummaryParameter ZP-Zolmitriptan 1.9 mg Receptor (μg) 1585 ± 25  Dermis (μg)6.081 ± 0.460 Epi (μg) 6.054 ± 2.258 St. Corn. (μg) 0.929 ± 0.303 S.Wash (μg) 48.74 ± 20.74 Patch (μg) 62.11 ± 6.90  Receptor (%) 83.41 ±1.33  Dermis (%) 0.320 ± 0.024 Epi (%) 0.319 ± 0.119 St. Corn. (%) 0.049± 0.016 S. Wash (%) 2.565 ± 1.092 Patch (%) 3.269 ± 0.363 Total Recovery(%) 89.94 ± 2.41 

Conclusion and Discussion.

Total absorbed zolmitriptan through the skin to the receptor solutionwas found to be 83.41±1.33% for the 1.9 mg patch. Peak flux occurred atapproximately 4 minutes after application with a peak flux of 849.4±42.1μg/cm²/hr. Less than 1% of the zolmitriptan was recovered from the threeskin layers at the end of the dose duration period. Mass balance wasfound to be approximately 90% of the applied dose.

Example 3—M207 Patch Stability

M207 patch assemblies were irradiated by e-beam and gamma irradiation upto 25 kGy dose. Subsequent irradiated patch assemblies were placed onstability at storage conditions of 25° C./60% RH and 40° C./75% RH.Results of the e-beam and gamma irradiated M207 patches are shown inTables 11-17.

TABLE 11 Purity of non-irradiated and e-beam irradiated ZolmitriptanPatches stored at 25° C./ 60% RH and 40° C./75% RH (L/N 203149) Purityby Temperature RP-HPLC Time (Month) Treatment (° C.) (%) 0 1 3 6 9 12 18Control 25 avg ± std 99.93 ± 100.00 ± 99.90 ± 99.91 ± 99.88 ± 99.92 ±99.90 ± (Non- 0.03 0.00 0.06 0.03 0.03 0.03 0.01 Irradiated) 40 avg ±std 99.93 ± 100.00 ± 99.91 ± 99.91 ± 0.03 0.00 0.01 0.02 Irradiated 25avg ± std 99.89 ± 100.00 ± 99.93 ± 99.88 ± 99.84 ± 99.77 ± 99.82 ± 0.050.00 0.01 0.02 0.03 0.02 0.01 40 avg ± std 99.89 ± 100.00 ± 99.93 ±99.88 ± 0.05 0.00 0.01 0.01

TABLE 12 ZP-Zolmitriptan content of non-irradiated and e-beam irradiatedZolmitriptan Patches stored at 25° C./60% RH and 40° C./75% RH (L/N203149) Temperature Content Time (Month) Treatment (° C.) (mg/patch) 0 13 6 9 12 18 Non-IR 25 avg 1.709 1.698 1.740 1.771 1.701 1.758 1.870 %RSD 6.0 3.8 8.0 2.2 5.9 12.6 2.7 40 avg 1.709 1.657 1.729 1.778 % RSD6.0 9.2 12.1 7.2 E-beam 25 avg 1.671 1.813 1.714 1.687 1.670 1.927 1.818IR % RSD 7.9 8.6 5.8 10.1 5.3 5.6 5.4 (19-24 kGy) 40 avg 1.671 1.6861.801 1.781 % RSD 7.9 7.7 4.3 5.3

TABLE 13 Purity of gamma irradiated Zolmitriptan Patches stored at 25°C./60% RH and 40° C./75% RH (L/N 203154) Temperature Purity Time (Month)Treatment (° C.) (%) 0 1 3 6 9 12 Irradiated 25 avg ± std 100.00 ± 0.0099.95 ± 0.00 99.90 ± 0.01 99.87 ± 0.00 99.77 ± 0.02 99.79 ± 0.01 40 avg± std 100.00 ± 0.00 99.93 ± 0.01 99.90 ± 0.01 99.86 ± 0.00

TABLE 14 ZP-Zolmitriptan content of non-irradiated and γ-irradiatedZolmitriptan Patches stored at 25° C./60% RH and 40° C./75% RH (L/N203154) Temperature Content Time (Month) Treatment (° C.) (mg/patch) 0 13 6 9 12 Gamma 25 avg 1.855 1.690 1.771 2.006 1.719 1.876 IR % RSD 4.223.5 2.4 1.8 13.5 4.5 (25 kGy) 40 avg 1.855 1.895 1.818 1.817 % RSD 4.27.6 11.6 1.1 Non-IR 25 avg 1.918 ND 1.874 2.001 1.840 1.950 % RSD 10.07.4 4.3 3.4 6.7 40 avg 1.918 1.955 1.895 % RSD 10.6 5.1 7.5 ND = NotDetermined.

TABLE 15 Total Impurity of non-irradiated and e-beam irradiatedZolmitriptan Patches stored at 25° C./60% RH and 40° C./75% RH (L/N203122) Total Temperature Impurities Time (Month) Treatment (° C.) (%) 01 3 6 9 12 Non-IR 25 avg ± std 0.06 ± 0.02 0.06 ± 0.02 0.07 ± 0.02 0.01± 0.03 0.00 ± 0.00 0.00 ± 0.00 40 avg ± std 0.06 ± 0.02 0.06 ± 0.03 0.05± 0.01 0.02 ± 0.04 E-beam IR 25 avg ± std 0.06 ± 0.01 0.06 ± 0.00 0.06 ±0.00 0.01 ± 0.03 0.00 ± 0.00 0.00 ± 0.00 (21 kGy) 40 avg ± std 0.06 ±0.01 0.09 ± 0.03 0.10 ± 0.04 0.02 ± 0.04

TABLE 16 ZP-Zolmitriptan content of non-irradiated and e-beam irradiatedZolmitriptan Patches stored at 25°C./60% RH and 40°C./75% RH (L/N203122) Temperature Content Time (Month) Treatment (° C.) (mg/patch) 0 13 6 9 12 Non-IR 25 avg 1.194 1.235 1.198 1.343 1.286 1.326 % RSD 10.410.7 7.5 6.4 8.5 5.7 40 avg 1.194 1.236 1.279 1.315 % RSD 10.4 7.5 8.75.7 E-beam IR 25 avg 1.212 1.130 1.169 1.255 1.251 1.283 (21 kGy) % RSD6.0 3.3 6.3 7.7 7.7 4.9 40 avg 1.212 1.181 1.191 1.144 % RSD 6.0 6.211.7 3.1

Solid-state physical stability was evaluated by XRD. Phase changes inamorphous vs. crystalline for zolmitriptan coating were examined by XRDanalysis. M207 1.9 mg patches at initial time point (TO), 6 month and 12month storage were analyzed. The drug coating was amorphous for bothnon-irradiated and gamma irradiated patches at TO. Gamma irradiatedzolmitriptan patches stored at 25° C./60% RH for 12 months and 40°C./75% RH showed similar XRD pattern to that of TO patches. Percentcrystallinity was calculated with peak profile fitting and the resultsare summarized in Table 16, below. No crystalline phase was detected forzolmitriptan formulation solids coated on gamma-irradiated patchesstored under both intended (25° C./60% RH) and accelerated storageconditions (40° C./75% RH) for 12 and 6 months respectively.

TABLE 17 Phase identification and percent crystallinity forgamma-irradiated M207 1.9 mg (L/N0203154-gamma) Stability ConditionPhase Present % Crystallinity T0 Ti • Titanium 100% (Ti) Hexagonal, S.G:P63/mmc (194) 0% (drug) Phase Info [01-089-3725] Amorphous material(drug coating) 6 months Ti • Titanium 100% (Ti) storage at Hexagonal,S.G: P63/mmc (194) 0% (drug) 25° C./60% RH Phase Info [01-089-3725]Amorphous material (drug coating) 6 months Ti • Titanium 100% (Ti)storage at Hexagonal, S.G: P63/mmc (194) 0% (drug) 40° C./75% RH PhaseInfo [01-089-3725] Amorphous material (drug coating) 12 months Ti •Titanium 100% (Ti) storage at Hexagonal, S.G: P63/mmc (194) 0% (drug)25° C./60% RH Phase Info [01-089-3725] Amorphous material (drug coating)

As described herein, zolmitriptan coated microneedles were exposed to adose of radiation in the range of approximately 7-30 kGy. Morepreferably in the range of 15-30 kGy to a sterility assurance level of10⁻⁵ to 10′. Table 17 shows 12 month stability results of irradiated andnon-irradiated zolmitriptan patches that were stored at 25° C. and 40°C.

Example 4—Drug-Device Combination Product

A novel drug-device combination product (M207) was made according to thepresent disclosure. M207 is an intracutaneous delivery system comprisinga disposable titanium microprojection member centered on an adhesivebacking to form a patch. This patch was mounted in a plastic retainerring to form a patch assembly. The patch is comprised of microneedlesthat are coated with the drug product formulation and dried. Theretainer ring facilitates mounting of the patch to the bottom of ahandheld applicator. This applicator ensures the patch is applied with adefined application energy to the site of administration. Thecombination of the patch assembly and the applicator comprises theintracutaneous delivery system. The applicator is held in one's hand toapply the patch. The applicator cap is twisted to unlock the applicator.When the applicator is pressed against the skin, a plunger pushes thepatch out of the retainer ring and applies it to the skin.

When one applies the patch to the skin, the patch stays on the skin andthe plastic ring stays on the applicator and is later detached andthrown away. The delivery system was designed to rapidly deliver a 1 mg,1.9 mg, or 3.8 mg dose of zolmitriptan intracutaneously. The unitformulas for the M207 drug products are provided in Table 18.

TABLE 18 Unit Formula for M207 Drug Product Amount per 1 mg Amount perComponent Unit (mg/patch) 1.9 mg Unit Function Zolmitriptan 1 1.9 ActiveTartaric acid 0.3 0.6 pH modifier Nitrogen N/A N/A Inert atmosphere forstorage

The zolmitriptan-coated titanium microneedle array is a 3 cm² arrayconsisting of about 1987 or about 997 titanium microneedles for the 1.9mg or 1 mg drug product, respectively. It is affixed to an approximately5 cm² adhesive patch. The patch may be mounted inside a polycarbonateplastic retainer ring with a co-molded desiccant. The desiccant mayalternatively attached to the lid of foil pouch. The completed patchassembly is packaged in a dry nitrogen-purged foil pouch. The userprepares the patch for application by pressing the handheld applicatoronto the patch assembly. The applicator comprises a spring-loaded pistonfor applying the patch to the user's skin (FIGS. 4(A), 4(B), and5(A)-(E)). The applicator is unlocked by twisting the outer griprelative to the base from the #1 position to #2 position (FIG. 5(C)).The user applies the patch by pressing the applicator mounted patchassembly onto the skin site. The applicator releases its piston at asufficient impact energy, for example, about 0.26 Joules. The pistonbreaks the patch from the retainer ring and applies the patch to theskin with the prescribed impact energy density to ensure reproduciblepatch application. The applicator is designed to ensure that the sameforce is applied for each delivery and across different users.

The drug-coated microneedles penetrate or pierce the stratum corneum ofthe skin, enabling drug delivery. Upon administration, the solidzolmitriptan coating rapidly dissolves off of the microneedles in theinterstitial fluid in the skin to form a solution and is available forabsorption. The patch is removed after about 30 minutes.

The M207 system components are listed in Table 19:

TABLE 19 M207 System Components Formulation Contact Component MaterialFunction Patch Assembly and Pouch Primary Container Closure MicroneedleTitanium Microneedles hold drug Array formulation and pierce the stratumcorneum to enable Adhesive Patch Acrylate adhesive Affixes themicroneedle with polyethylene array to the inner ring backing prior todelivery. Holds array in position Inner Ring None Holds adhesive patch.Assembled to Outer Outer Ring None Desiccant co-molded with the outerring removes residual moisture from patch and maintains low-moistureenvironment during storage. Ring engages with applicator to Pouch NoneLow oxygen and low vapor permeability, protects against light. NitrogenNitrogen Inert, low-moisture atmosphere for drug Desiccant Maintains lowmoisture atmosphere Provides consistent energy for repeatable patchappli- Applicator cation to a defined depth of Top None Covers internalworkings. Upper Post None Limits travel of piston. Engages with cap tocreate ratchet mechanism for unidirectional Twist Cup, Inner NoneContains ledge for lockout function, and indexing cams which forcerotation and align Twist Cup, Outer None Grip surface for userinterface. Contains window for visualizing indicators. Doming SpringNone Provides consistent force to dome skin and trigger the device.After patch application Inner Cup None Provides structural support andbearing Lower Post None Provides guidance for piston and holds theTrigger None Latches on piston to retain during compression of pistonspring. During user actuation, at point of full compression, the ClearBottom None Engages with Outer Ring of Patch. Holds applicator assemblytogether. Piston Spring None Provides energy for application of AdhesivePiston None Motive member which transfers energy from Piston Spring toAdhesive Patch, enabling

Example 5—Human PK Clinical Trial

An evaluation in humans of the M207 product was performed. In this Phase1 study, commercially available oral zolmitriptan tablet 2.5 mg andsubcutaneous sumatriptan 6.0 mg were included as comparators. Asdescribed in the examples above, M207 consists of a titanium array ofmicroneedles coated with zolmitriptan, administered intracutaneously viaa patch applied by a specialized applicator. The aim of this trial wasto provide information on the pharmacokinetics and tolerability of theM207 system. Assessment of the tolerability of various doses ofintracutaneous zolmitriptan to a standard oral dose (2.5 mg) ofzolmitriptan was also completed together with an assessment of reactionsat the application site.

Specifically, the study compared single administrations of five regimensof M207, as well as 2.5 mg of oral zolmitriptan tablet and 6.0 mg ofsubcutaneous sumatriptan in a 7-way crossover design in 20 healthyvolunteers. Analysis of the plasma samples for concentrations ofzolmitriptan, N-desmethyl zolmitriptan and sumatriptan were performed atQuest Pharmaceutical Services in Groningen, Holland, by assays known inthe art. In this study, the administration of M207 systems resulted in arapid time to maximum concentration (T_(max)), comparable exposure toorally administered zolmitriptan, but displayed reduced exposure to themajor metabolite, N-desmethyl zolmitriptan. The doses assessed in thisstudy using the M207 system were 0.48 mg, 0.96 mg, 1.9 mg, and 3.8 mg.

The first 4 administrations of zolmitriptan utilized 5 cm² patches and a0.26 Joule applicator in the intracutaneous microneedle system describedherein. The final treatment administered was 3.8 mg on a 10 cm² patchusing an applicator with 0.52 Joule of application energy in theintracutaneous microneedle system described herein. The products testedwere:

M207 0.48 mg Patch Assembly:

The zolmitriptan 0.48 mg patch consisted of a 3 cm² titanium array ofmicroprojections that were nominally 340 μm in length coated with 0.48mg of zolmitriptan. The array was applied to the center of a 5 cm² tanadhesive backing to form the patch. The patch was attached to theinterior of a white to off-white polycarbonate ring co-molded with adesiccant, and this patch assembly was packaged in a foil pouch.

M207 1.9 mg Patch Assembly:

The zolmitriptan 1.9 mg patch consisted of a 3 cm² titanium array ofmicroprojections that were nominally 340 μm in length coated with 1.9 mgof zolmitriptan. The array was applied to the center of a 5 cm² tanadhesive backing to form the patch. The patch was attached to theinterior of a white to off-white polycarbonate ring co-molded with adesiccant, and this patch assembly was packaged in a foil pouch.

M207 3.8 mg Patch Assembly:

The zolmitriptan 3.8 mg patch consisted of a 5.5 cm² titanium array ofmicroprojections that were nominally 340 μm in length coated with 3.8 mgof zolmitriptan. The array was applied to the center of a 10 cm² tanadhesive backing to form the patch. The patch was attached to theinterior of a white to off-white polycarbonate ring co-molded with adesiccant, and this patch assembly was packaged in a foil pouch.

Study Design

This was a single-center, open-label, randomized five-way crossoverstudy (Part 1) followed by a sequential study of two additionaltreatments (Parts 2 and 3). After obtaining informed consent andestablishing eligibility, each subject received each of the seven studytreatments once, followed by in-clinic monitoring and extensive bloodsample collection for pharmacokinetic analysis. Dosing days in Part 1occurred between 48-120 hours apart, until completion of dosing forTreatments A-E (see Table 20) in randomized order per the treatmentsequence tables. Plasma samples from the initial dosing days were sentto the analytical laboratory for analysis, and tolerability for each ofthe dose levels was summarized. Tolerability was judged to beacceptable, and subjects returned for Part 2. During Part 2, subjectsreceived intracutaneous administered zolmitriptan in 1.9 mg×2 patches(applied with the same 0.26 J applicator used in Part 1), and completedidentical procedures to Part 1. During Part 3, subjects received asingle 3.8 mg patch (applied with a 0.52 J applicator) and alsocompleted identical procedures to the previous dosing days. Aftercompletion of the seven dosing days, subjects were assessed one finaltime and dismissed from the study.

The treatments used in the trial were as listed in Table 20 below:

TABLE 20 Treatments Used In Trial TREATMENTS Part 1 (Cross-Over Design)Treatment A M207 intracutaneous system 0.48 mg Treatment B M207intracutaneous system 0.48 mg × 2 Treatment C M207 intracutaneous system1.9 mg Treatment D Zolmitriptan 2.5 mg oral Treatment E Sumatriptan 6.0mg SC Part 2 Treatment F Zolmitriptan intracutaneous system 1.9 mg × 2Part 3 Treatment G Zolmitriptan intracutaneous system 3.8 mg

Twenty subjects were enrolled in the study, 10 males and 10 females. Thesubjects mean age was 29 years ±3.5 years with a mean BMI of 24.4±3.5.With the exception of one subject who missed one treatment visit, allsubjects completed all 7 treatment visits of the study, and received all7 study treatments. In two subjects (#1010 in Treatment A and #2010 inTreatment D), very few post-dose blood samples were collected at onevisit due to difficulties with venous access, but for all the rest ofthe subjects, virtually all of the scheduled pharmacokinetic bloodsamples (14 per visit) were collected for analyses.

Tolerability in Part 1 was considered acceptable, and following a reviewof the safety data and pharmacokinetic data from the first five dosingperiods, and a discussion between the sponsor and the PrincipalInvestigator, subjects proceeded to Parts 2 and 3 and completed thosevisits. The collected serum was analyzed for zolmitriptan andN-desmethyl zolmitriptan using methods well known in the art, such asusing a liquid chromatography-mass spectrometry (LC-MS-MS) method.

Pharmacokinetics

The M207 patch was well-tolerated and rapid absorption was observedwhich were believed to potentially translate to fast pain relief formigraine or cluster headache patients. The Phase 1 results demonstratingthe fast absorption of M207 that is characteristic of Zosano'smicroneedle patch and applicator system are illustrated below:

TABLE 21 M207 Characteristic of Zosano's Microneedle Patch C_(max)T_(max) AUC_(0-2 hr) AUC_(0-last) (SD) (range) (SD) (SD) ng/ml min ng/mlhour ng/ml hour A M207 0.48 mg 1.8 (0.53) 20 (2-30) 2.1 (0.73) 2.8(1.36) B M207 2 × 0.48 mg 3.7 (1.05) 20 (2-30) 4.2 (0.95) 6.5 (1.97) CM207 1.9 mg 6.8 (2.75) 20 (2-30) 7.4 (2.53) 12.3 (4.31) F M207 2 × 1.9mg 14.6 (4.46) 17.5 (2-30) 16.4 (5.34) 27.8 (9.93) G M207 3.8 mg 22.6(14.00) 15 (2-30) 19.3 (5.37) 31.7 (8.35) D Zolmitriptan 2.5 mg 3.8(1.51) 60 (30-240) 4.7 (2.24) 22.2 (10.79) Oral Tablet

The mean plasma concentration versus time data, for each of the six (6)zolmitriptan regimens administered are shown in FIGS. 7 and 8. FIG. 7shows the results for the entire 24 hours sampling period and FIG. 8shows the results for the first two hours post study drug administrationonly. Both figures include the subcutaneous sumatriptan concentrationvs. time data (scaled for display purposes to illustrate time course).The results following SC sumatriptan were similar to several publishedstudies of this dose and route of administration.

Based on the results presented in FIGS. 7 and 8, plasma levels ofzolmitriptan following zolmitriptan intracutaneous application weredose-dependent, and the absorption following patch application was muchfaster than that seen following administration of the 2.5 mg tablet. Theplasma levels seen after the single larger 3.8 mg patch were higher thanthose seen following 2×1.9 mg patches. Plots of dose linearity forzolmitriptan C_(max), AUC_(t), and AUC_(inf) are shown in FIGS. 9, 10,and 18 (excluding the larger 3.8 mg patch). Plots of dose linearity forN-desmethyl zolmitriptan C_(max), AUC_(t), and AUC_(inf) are shown inFIGS. 22-24 (excluding the larger 3.8 mg patch). Excellent doselinearity was observed over the range of doses evaluated. The calculatedkey mean (median for T_(max)) pharmacokinetic parameters for thezolmitriptan regimens and subcutaneous sumatriptan are shown in thefollowing Table 22.

TABLE 22 Zolmitriptan Group PK values GROUP PARAMETER T_(max) t_(1/2)C_(max) AUC_(t) AUC_(inf) AUC_(2hrs) A N 19 19 19 19 19 19 (0.48 mg)Mean 17.32 69.06 1.84 2.81 3.81 2.11 (SD) (12.10) (16.26) (0.53) (1.36)(1.46) (0.73) Median 20 64.62 1.8 2.78 3.78 2.11 Range 2, 30 46.2,101.46 0.64, 2.93 0.39, 6.23 1.37, 7.5 0.39, 3.53 CV % 69.90% 23.50%29.00% 48.30% 38.30% 34.40% B N 20 20 20 20 20 20 (0.48 mg × 2) Mean18.35 77.22 3.70 6.45 7.71 4.15 (SD) (11.23) (17.46) (1.05) (1.97)(2.03) (0.95) Median 20 81.96 3.63 6.55 7.85 4.19 Range 2, 30 41.76,96.84 1.96, 6.32 3.16, 9.52 4.22, 10.98 2.46, 5.81 CV % 61.20% 22.60%28.40% 30.50% 26.30% 22.90% C N 20 20 20 20 20 20 (1.9 mg) Mean 17.8587.84 6.76 12.29 14.14 7.36 (SD) (12.58) (16.74) (2.75) (4.31) (4.54)(2.53) Median 20.00 84.72 6.40 12.69 14.50 7.75 Range 2, 30 61.20,124.98 3.14, 13.20 5.01 19.59 6.55, 20.95 3.44, 11.46 CV % 70.50% 19.10%40.60% 35.10% 32.10% 34.40% D N 19 18 19 19 18 19 (2.5 mg oral) Mean107.37 196.44 3.77 22.20 27.19 4.72 (SD) (76.37) (48.18) (151) (10.79)(11.34) (2.24) Median 60 196.8 3.7 22.65 27.1 4.92 Range 30, 240 117.84,288.72 1.66, 6.77 7.47, 46.85 14.33, 55.14 1.73, 9.97 CV % 71.10% 24.50%40.00% 48.60% 41.70% 47.50% F N 20 20 20 20 20 20 (1.9 mg × 2) Mean17.10 91.70 14.61 27.77 30.12 16.44 (SD) (11.82) (18.7) (4.46) (9.93)(10.13) (5.34) Median 17.5 96.2 14.15 28.05 30.61 16.68 Range 2, 3060.90, 123.10 7.09, 25.50 13.24, 51.33 14.50, 53.38 7.38, 29.32 CV %69.10% 20.40% 30.50% 35.70% 33.60% 32.50% G N 20 20 20 20 20 20 (3.8 mg)Mean 16.10 91.00 22.56 31.65 33.81 19.33 (SD) (11.63) (18.80) (14.00)(8.35) (7.95) (5.37) Median 15 87.20 19.9 29.93 32.2 18.42 Range 2, 3060.90, 130.60 9.03, 70.4 16.90, 44.33 19.01, 46.41 9.96, 29.55 CV %72.20% 20.60% 62.10% 26.40% 23.50% 27.80%

Likely most relevant to the potential utility of this product for thetreatment of migraine or cluster headache is the T_(max) for theintracutaneous administered zolmitriptan regimens, showing much morerapid absorption of the zolmitriptan from intracutaneous administration,than from oral administration.

The pharmacokinetic parameters following intracutaneous administeredzolmitriptan were on average very similar when comparing the results inmale subjects with the results seen in female subjects, as shown inFIGS. 11 and 12.

The active metabolite, N-desmethyl zolmitriptan was detectable in allsubjects dosed at the five higher dose regimens. The N-desmethylzolmitriptan pharmacokinetic parameters for each of the zolmitriptanregimens are shown in the following Table 23.

TABLE 23 N-desmethyl Zolmitriptan Metabolite Group PK value GROUPPARAMETER T_(max) t_(1/2) C_(max) AUC_(t) AUC_(inf) AUC_(2hrs) A N 18 1618 18 16 18 (0.48 mg) Mean 65.00 198.41 0.22 0.70 1.38 0.31 (SD) (18.55)(98.20) (0.05) (0.31) (0.476) (0.10) Median 60.00 173.70 0.22 0.78 1.420.32 Range 30.00, 120.00 86.23, 511.18 0.14, 0.37 0.19, 1.26 0.68, 2.500.10, 0.51 CV % 28.5% 49.5% 24.6% 44.5% 34.5% 31.8% B N 20 20 20 20 2020 (0.48 mg × 2) Mean 57.75 196.71 0.42 1.56 2.43 0.62 (SD) (14.00)(104.70) (0.11) (0.57) (0.78) (0.17) Median 60.00 168.2 0.43 1.42 2.490.61 Range 15.00, 90.00 122.4, 592.5 0.23, 0.60 0.94, 3.39 1.44, 4.420.32, 0.94 CV % 24.2% 53.2% 27.0% 36.4% 31.9% 26.9% C N 20 20 20 20 2020 (1.9 mg) Mean 61.50 182.9 0.74 3.01 3.65 1.07 (SD) (18.14) (59.2)(0.31) (1.29) (1.22) (0.47) Median 60.00 165.7 0.81 3.03 3.62 1.12 Range30.00, 90.00 87.3, 282.8 0.29, 1.12 1.10, 5.37 1.58, 5.91 0.41, 1.64 CV% 29.5% 32.3% 42.8% 42.8% 33.4% 44.3% D N 19 19 19 19 19 19 (2.5 mgoral) Mean 162.63 192.9 2.08 13.71 14.55 2.31 (SD) (77.02) (68.1) (0.50)(2.91) (3.06) (0.93) Median 120.00 164.6 2.04 13.76 14.31 2.24 Range60.00, 240.00 127.9, 348.9 1.40, 3.40 9.39, 19.90 9.90, 20.58 0.73, 4.64CV % 47.4% 35.3% 24.1% 21.3% 21.0% 40.3% F N 20 20 20 20 20 20 (1.9 mg ×2) Mean 63.00 169.0 1.41 6.50 7.22 2.15 (SD) (13.42) (27.3) (0.46)(2.30) (2.34) (0.72) Median 60.00 162.2 1.62 6.75 7.52 2.24 Range 30.00,90.00 117.1, 215.3 0.65, 2.05 2.68, 10.74 3.43, 11.45 0.92, 3.45 CV %21.3% 16.1% 32.4% 35.4% 32.5% 33.3% G N 20 20 20 20 20 20 (3.8 mg) Mean54.74 162.0 1.77 7.55 8.17 2.66 (SD) (16.11) (31.30) (0.63) (1.98)(1.96) (0.83) Median 60.00 155.3 1.78 7.48 8.16 2.69 Range 20.00, 90.00111.1, 239.1 0.77, 3.54 3.39, 10.56 3.84, 11.18 1.19, 4.64 CV % 29.4%19.3% 35.5% 26.3% 24.0% 31.0%

The levels of N-desmethyl zolmitriptan were significantly lower afterM207 zolmitriptan intracutaneous administration than those seenfollowing oral administration (Treatment D).

PK parameters were summarized by treatment group using descriptivestatistics (arithmetic means, standard deviations, coefficients ofvariation, sample size, minimum, maximum, and median). In addition,geometric means and 95% confidence intervals (CIs) were calculated forAUC_(2 hrs), AUC_(t), AUC_(inf) and C_(max). For each of thezolmitriptan treatments, the ratio of AUC_(inf) N-desmethylzolmitriptan/AUC_(inf) zolmitriptan was calculated for each subject; agroup mean was determined.

Dose proportionality was evaluated for the three doses of M207; doseproportionality was not based solely on a strict statistical rule. Therelationship between dose and PK parameters of zolmitriptan wereexamined using a graphical approach and by descriptive statistics.Graphs of apparent dose linearity and proportionality of PK parameters(AUC_(t), AUC_(inf) and C_(max)) were compiled.

Rapid absorption of zolmitriptan was seen after intracutaneous patchapplication; mean peak plasma concentrations (T_(max)) occurred between16.1 and 18.4 minutes. This was similar to sumatriptan SC injection(12.5±4.4 minutes) and considerably quicker than zolmitriptan tablets(107.4±76.4 minutes [1.8±1.27 hours]).

The mean (±SD) elimination half life (t½) for M207 systems was 1.15±0.27hours up to 1.53±0.31 hours across the dose range of 0.48 mg to 3.8 mg,respectively. Elimination of zolmitriptan following zolmitriptan tablets(3.27±0.8 hours) was almost twice as slow as M207.

The mean (±SD) maximum plasma concentration (C_(max)) of zolmitriptantablets was 3.77±1.51 ng/mL. The administration of 2×0.48 mg patchesprovided an almost equivalent maximum concentration of 3.70±1.05 ng/mL;C_(max) for Group C (1.9 mg) administered as a single patch was almostdouble (6.76±2.75 ng/mL). Groups F and G produced maximum plasmaconcentrations 3.9 times (14.61±4.46 ng/mL) and 6 times (22.56±14.0ng/mL) that of zolmitriptan tablets, respectively.

Mean (±SD) total exposure (AUC_(inf)) was 3.81±1.46 ng·H/mL for M2070.48 mg and 33.81±7.95 ng·H/mL for M207 3.8 mg applied as singlepatches. Treatment with M207 patches in Groups F and G produced asimilar exposure (AUC_(inf)) to zolmitriptan tablets (30.12, 33.81ng·H/mL, respectively). The mean exposure (AUC_(inf)) for M207 wasproportional (y=8.31) to the dose for single patch administration. Theconcentration-time curve over zero to two hours for all treatments isdisplayed in FIG. 8 and zero to twenty-four hours in FIG. 7.

Plasma concentrations were slightly higher in males than females for thehigher doses, Group F (2×1.9 mg) and Group G (3.8 mg). There did notappear to be a difference between genders at lower doses (Groups A [0.48mg] to C [1.9 mg]).

The relative bioavailability of M207 systems was compared tozolmitriptan tablets using the following formula:

$F_{rel} = \frac{{{AUC}_{\inf}\left( {M\; 207} \right)} \times {Dose}\mspace{14mu} \left( {{Group}\mspace{14mu} D} \right)}{{AUC}_{\inf}\mspace{14mu} \left( {{Group}\mspace{14mu} D} \right) \times {Dose}\mspace{14mu} \left( {M\; 207} \right)}$

The mean total exposure for M207 intracutaneous microneedle systems wasless, relative to zolmitriptan tablets (range: 0.70-0.86). However, themean peak exposure was 2.35 to 3.73 fold higher for intracutaneouszolmitriptan compared to zolmitriptan tablets.

A summary of the key calculated pharmacokinetic parameters from thestudy are shown in Table 24.

TABLE 24 Mean (SD) PK parameters (0-24 hours) for All Treatments GroupFormulation T_(max) t_(1/2) C_(max) AUC_(inf) AUC_(t) AUC_(2hrs) F_(rel)F_(rel) (dose) Parameter (min) (H) (ng/mL) (ng · H/mL) (ng · H/mL) (ng ·H/mL) AUC_(inf) C_(max) A ZP-Zolmitriptan Mean 17.3 1.15 1.84 3.81 2.812.11 0.73 2.60 (0.48 mg) (SD) (12.1) (0.27) (0.53) (1.46) (1.36) (0.73)N = 19 B ZP-Zolmitriptan Mean 18.4 1.29 3.70 7.71 6.45 4.15 0.77 2.65(0.48 mg × 2) (SD) (11.2) (0.29) (1.05) (2.03) (1.97) (0.95) N = 20 CZP-Zolmitriptan Mean 17.9 1.46 6.76 14.14 12.29 7.36 0.70 2.35 (1.9 mg)(SD) 12.6 (0.28) (2.75) (4.54) (4.31) (2.53) N = 20 D Zolmitriptan oralMean 107.4 3.27 3.77 27.19 22.20 4.72 — — tablet (2.5 mg) (SD) 76.4(0.80) (1.51) (11.34) (10.79) (2.24) N = 19 E Sumatriptan SC Mean 12.51.14 88.80 105.23 100.88 70.88 — — (6.0 mg/0.5 mL) (SD) 4.4 (0.31)(27.56) (23.14) (23.29) (14.15) N = 20 F ZP-Zolmitriptan Mean 17.1 1.5314.61 30.12 27.77 16.44 0.74 2.63 (1.9 mg × 2) (SD) (11.8) (0.31) (4.46)(10.13) (9.93) (5.34) N = 20 G ZP-Zolmitriptan Mean 16.1 1.52 22.5633.81 31.65 19.33 0.86 3.73 (3.8 mg) (SD) (11.6) (0.31) (14.00) (7.95)(8.35) (5.37) N = 20

Approximately twice the amount of the active metabolite, N-desmethylzolmitriptan was formed following zolmitriptan oral administration (mean59.8±16%) compared to those seen following M207 (Table 25).

TABLE 25 N-desmethyl Zolmitriptan/Zolmitriptan Metabolite Ratio GROUPPARAMETER A B C D F G Metabolite ratio (0.48 mg) (0.48 mg × 2) (1.9 mg)(2.5 mg oral) (1.9 mg × (3.8 mg) N 16 20 20 18 20 20 Mean (%) 35.1 31.725.9 59.8 24.3 24.2 (SD) (10.1) (5.8) (3.6) (16.0) (4.2) (3.8) Median(%) 33.6 31.1 25.2 56.9 23.4 24.0 Range 23.1, 61.9 22.4, 46.2 19.5, 35.729.9, 89.4 17.6, 34.1 19.0, 32.1 (min, max %)

The relative bioavailability of the active metabolite, N-desmethylzolmitriptan produced for M207 patches was compared to zolmitriptantablets using the following formula:

$F_{rel} = \frac{N\text{-}{desmethyl}\mspace{14mu} {zolmitriptan}\mspace{14mu} {AUC}_{\inf}\mspace{14mu} \left( {M\; 207} \right) \times {Dose}\mspace{14mu} \left( {{Group}\mspace{14mu} D} \right)}{N\text{-}{desmethyl}\mspace{14mu} {zolmitriptan}\mspace{14mu} {AUC}_{\inf}\mspace{14mu} \left( {{Group}\mspace{14mu} D} \right) \times {Dose}\mspace{14mu} \left( {M\; 207} \right)}$

There was less conversion to the N-desmethyl zolmitriptan metabolite forM207 patches compared to zolmitriptan tabs (Fret AUC range: 0.32-0.46)and approximately 50% less rate of exposure for M207 patches compared tozolmitriptan tablets based the relative bioavailability of C_(max).

Plasma concentrations of the N-desmethyl metabolite reached maximum ataround 1 hour (range: 54.7-65.0 minutes) for M207 administered via theintracutaneous route compared to (162.6 minutes [2.71 H] forzolmitriptan tablets, FIG. 13. The elimination half life (t_(1/2)) forthe metabolite was comparable for all treatments including oraladministration (range 2.7 H to 3.31 H]). The concentration-time curvefrom 0-24 hours for N-desmethyl zolmitriptan is displayed in FIG. 14.

Mean maximum plasma concentration (C_(max)) for the M207 0.48 mg dosewas 0.22 ng/mL and 1.77 ng/mL for the 3.8 mg strength compared to 2.08ng/mL for zolmitriptan tablets. Mean AUC_(inf) was 1.38 ng·H/mL for the0.48 mg strength up to 8.17 ng·H/mL for the 3.8 mg strength versus 14.55ng·H/mL for zolmitriptan tablets. The extent (C_(max) and AUC_(inf)) ofthe N-desmethyl metabolite for M207 patches were directly proportional(y=0.4127 and 2.022, respectively) to the dose and considerably lowerthan that for zolmitriptan tablets. See FIGS. 19 and 21.

A summary of the mean pharmacokinetic parameters for N-desmethylzolmitriptan is detailed in Table 26.

TABLE 26 Mean (SD) PK parameters for N-desmethyl zolmitriptan metaboliteGroup Formulation T_(max) t_(1/2) C_(max) AUC_(inf) AUC_(t) F_(rel)F_(rel) (dose) Parameter (min) (H) (ng/mL) (ng · H/mL) (ng · H/mL)AUC_(inf) C_(max) A ZP-Zolmitriptan Mean 65.0 3.31 0.22 1.38 0.70 0.460.52 (0.48 mg) SD (18.6) (1.64) (0.05) (0.48) (0.31) B ZP-ZolmitriptanMean 57.8 3.28 0.42 2.43 1.56 0.43 0.52 (0.48 mg × 2) SD (14.0) (1.75)(0.11) (0.78) (0.57) C ZP-Zolmitriptan Mean 61.5 3.05 0.74 3.65 3.010.32 0.43 (1.9 mg) SD (18.1) (0.99) (0.32) (1.22) (129) D ZolmitriptanMean 162.6 3.22 2.08 14.55 13.71 — — oral tablet SD (77.0) (1.14) (0.50)(3.06) (2.91) (2.5 mg) F ZP-Zolmitriptan Mean 63.0 2.82 1.41 7.21 6.500.32 0.43 (1.9 mg × 2) SD (13.4) (0.45) (0.48) (2.34) (2.30) GZP-Zolmitriptan Mean 54.7 2.70 1.77 8.17 7.55 0.36 0.52 (3.8 mg) SD(16.1) (0.52) (0.63) (1.96) (1.98)

M207 also tended to have less intragroup variability (as indicated bythe CV % s) for the AUC_(inf) parameter compared to the zolmitriptantablets.

Dose Linearity for M207 System Administration

A positive linear association and was seen for C_(max) (y=4.81), AUC_(t)(y=7.61) and AUC_(inf) (y=8.31) for both single (0.48 mg, 1.9 mg and 3.8mg) and multiple (0.48 mg×2 and 1.9 mg×2) system administration. SeeFIGS. 15-17. At the lower end of the dosing range (0.48 mg×2),concentrations of both the zolmitriptan and the N-desmethyl zolmitriptanmetabolite were very comparable. However, at the highest dose (1.9mg×2), plasma concentrations achieved with multiple patch administrationwere slightly less than that with a single patch (and the 0.52 Jadministration force) for both zolmitriptan and the N-desmethylzolmitriptan. For N-desmethyl zolmitriptan, see FIGS. 19-21.

M207 patch administration resulted in rapid peak plasma concentrations(T_(max)) that occurred within 20 minutes of patch application. Thiscompared favorably with 12.5 minutes for SC sumatriptan and offers aconsiderable improvement over conventional release oral zolmitriptantablets (1.8 hours). Elimination rate (t_(1/2)) for M207 was shorter,approximately twice the rate of zolmitriptan tablets (1.2-1.5 hoursversus 3.3 hours).

C_(max) for zolmitriptan tablets was 3.77 ng/mL. Treatment with M207patches in Groups C (1.9 mg), F (1.9 mg×2) and G (3.8 mg) produced 1.8,3.9 and 6 times higher mean peak plasma concentration than zolmitriptan2.5 mg tablets. Multiple patch administration with 2×0.48 mg M207produced a comparable C_(max) (3.70 ng/mL) to oral zolmitriptan tablets.

Treatment with M207 patches in Groups F and G produced a similarexposure (AUC_(inf)) to oral zolmitriptan tablets (30.12, 33.81 and27.19 ng·H/mL, respectively). However, the mean total exposure(AUC_(inf)) for M207 patches was less (0.700-0.86) and the mean peakexposure (C_(max)) was 2.35 to 3.73 fold higher, relative to oralzolmitriptan tablets.

The time to peak plasma concentration of the N-desmethyl metabolite fromM207 was considerably faster at around 1 hour versus 2.7 hours for oralzolmitriptan. However, the extent of metabolite produced from M207 wasabout 50% less than oral zolmitriptan tablets. The key PK findings aresummarized in Table 27 below.

TABLE 27 Key Pharmacokinetic Parameters Dose C_(max) (SD) T_(max) MedAUC_(0-2hr) (SD) AUC_(0-last) (SD) AUC_(0-last) BA v (mg) ng/mL (Range)ng/mL hour ng/mL hour Dose Oral A (ZP Zolmi) 0.48 1.8 (0.53) 20 (2-30)2.1 (0.73) 2.8 (1.36) 5.8  67% B (ZP Zolmi) 0.48 × 2 3.7 (1.05) 20(2-30) 4.2 (0.95) 6.5 (1.97) 7.5  87% C (ZP Zolmi) 1.9 6.8 (2.75) 20(2-30) 7.4 (2.53) 12.3 (4.31) 6.5  76% F (ZP Zolmi)  1.9 × 2 14.6 (4.46)17.5 (2-30) 16.4 (5.34) 27.8 (9.93) 7.3  85% G (ZP Zolmi) 3.8 22.6(14.00) 15 (2-30) 19.3 (5.37) 31.7 (8.35) 8.3  97% D (Oral Zolmi) 2.53.8 (1.51) 60 (30-240) 4.7 (2.24) 22.2 (10.79) 8.6 100% E (SC Suma) 6.088.8 (27.56) 10 (5-20) 70.9 (14.15) 100.9 (23.29) 16.8

Perhaps most relevant to the potential utility of this product for thetreatment of migraine or cluster headache is the T_(max) for the M207regimens, showing much more rapid absorption of the zolmitriptan fromintracutaneous administration, than from oral administration.

A comparison of exposure is provided in Table 28 below.

TABLE 28 Comparison of exposure - M207 vs. Oral Zolmitriptan (Phase 1Study and Literature Comparisons) C_(max) AUC_(0-last) Treatment (Study)(ng/ml) (ng/ml*hr) M207 0.96 mg (Study) 3.73 6.5 M207 1.9 mg (Study)6.40 12.3 M207 2 × 1.9 mg (Study) 14.6 27.8 Zolmitriptan 2.5 mg oral 3.822.2 (Study) Zolmitriptan 10 mg oral 16.6(M)-20.9(F) 84.4(M)-108.6(F)(Seaber1997)

There was excellent dose linearity observed for high and low dose forC_(max) and AUC_(inf). M207 was well-tolerated. Adverse events (AE) werepredominantly mild (87%), of a short (<24 hour) duration and themajority were consistent with events previously reported withzolmitriptan (88%). There were no severe or serious AEs. Transientchanges in both systolic and diastolic blood pressure occurred, and forboth systolic and diastolic blood pressure, the pressure values returnedto pre treatment levels 1-2 hours after drug administration. Nosignificant ECG changes occurred. Application of the patch was toleratedwell with mostly mild to moderate reactions that resolved after 24hours. Local tolerability of the 3.8 mg patch applied with greater force(0.52 J) was not as favorable as the other regimens.

The M207 intracutaneous delivery system offers pharmacokineticadvantages over zolmitriptan tablets that should result in a fasteronset of action, comparable exposure and reduced first-pass metabolismwith the lowered potential for drug interactions and adverse events.Importantly, delivery is via a method that does not involve thegastrointestinal route or the injection method. Further comparison tothe zolmitriptan conventional oral tablet is set forth below in Tables29 and 30.

TABLE 29 Ratios of M207 vs. Group D (oral zolmitriptan 2.5 mg tablets)PARAMETER GROUP (dose) Ratios vs. Group D A B C F G (2.5 mg) (0.48 mg)(0.48 mg × 2) (1.9 mg) (1.9 mg × 2) (3.8 mg) C_(max) Ratio vs. D 0.501.02 1.79 4.00 5.56 90% CI 0.42, 0.60 0.85, 1.2 1.52, 2.13 3.23, 5.004.55, 7.14 AUC₁ Ratio vs. D 0.12 0.31 0.58 1.32 1.55 90% CI 0.10, 0.150.25, 0.38 0.47, 0.71 1.09, 1.59 1.28, 1.87 AUC_(inf) Ratio vs. D 0.140.3 0.53 1.15 1.32 90% CI 0.12, 0.16 0.25, 0.35 0.45, 0.62 0.97, 1.351.12, 1.56 AUC_(2hrs) Ratio vs. D 0.46 0.96 1.63 3.69 4.41 90% CI 0.38,0.55 0.80, 1.15 1.36, 1.96 3.04, 4.48 3.63, 5.36

TABLE 30 Ratios of N-desmethyl Zolmitriptan vs. Group D (oralzolmitriptan 2.5 mg tablets) PARAMETER GROUP (dose) Ratio vs. Group D AB C F G (2.5 mg oral) (0.48 mg) (0.48 mg × 2) (1.9 mg) (1.9 mg × 2) (3.8mg) C_(max) Ratio vs D 0.10 0.02 0.32 0.65 0.79 90% CI 0.09, 0.11 0.18,0.23 0.26, 0.37 0.56, 076 0.68, 0.93 AUC₁ Ratio vs. D 0.04 0.11 0.200.45 0.54 90% CI 0.04, 0.05 0.09, 0.13 0.17, 0.24 0.39, 0.53 0.46, 0.63AUC_(inf) Ratio vs. D 0.09 0.16 0.24 0.48 0.55 90% CI 0.08, 0.10 0.14,0.19 0.21, 0.28 0.42, 0.55 0.48, 0.63 AUC_(2hrs) Ratio vs. D 0.13 0.280.45 0.93 1.14 90% CI 0.11, 0.15 0.24, 0.32 0.38, 0.52 0.78, 1.13 0.95,1.38

Example 5—In Vivo Pig Study

The M207 patch was tested in swine. Intravenously administeredzolmitriptan was used as a control. The inner thigh of the swine wasused as the site of administration.

Determination of Zolmitriptan by LC/MS/MS Method

The analysis for zolmitriptan from used patches, skin swabs and plasmaPK samples was performed using established in-house LC/MS/MS methods.The low limit of quantitation (LLOQ) and high-limit of quantitation(HLOQ) were 0.1 and 1000 ng/mL, respectively. A four minute methodutilizing high performance liquid chromatography-electrosprayionization-tandem mass spectrometry (HPLC-ESI-MS/MS) was developed forquantitation of zolmitriptan and its two major metabolites in HGPplasma. The instrumentation consist of Agilent® 1200 pumps, CTC PAL®Autosampler with cooling stack, AB Sciex® TurboV® ESI source, and API4000® mass spectrometer.

All plasma samples and standards were first protein precipitated using100% methanol and then diluted with 30% solution of acetonitrile at 1:2ratio (Plasma: 30% ACN), 20 μL of this solution was injected intoautosample. The autosample was equipped with a 100 μL syringe and a 100μL loop. The syring and the loop were washed twice with solvent 1 (0.2%formic acid) and solvent 2 (0.2% formic acid in acetonitrile) betweeneach injections.

A 10-port 2 position Valco® valve was placed in-line with the massspectrometer equipped with a guard cartridge (Zorbax 300SB-C8, 12.5×4.6mm) used for on-line solid phase extraction (SPE). This valve was setupsuch that in the “load” position, the sample was injected onto thecartridge and was washed with 10% mobile phase B for 30 seconds, nextthe valve was switched into the “inject” position, where the cleanedsample would eluted from the SPE cartridge in reversed direction ontothe analytical column (Luna PFP(2), 100 A, 5 μm, 50×2 mm) and into themass spectrometer.

The HPLC method used was a reversed phase gradient method (0.0 min, 10%B; 0.5 min, 10% B; 1.0 min, 40% B; 1.7 min, 40% B; 2.1 min, 10% B; 4.0min, 10% B). HPLC mobile phases consist of 20 mM Ammonium Acetate asmobile phase A, and 80% acetonitrile in 20% 20 mM Ammonium Acetate asmobile phase B. The source setting for all analysis were the following:Collision gas (CAD)=12; Curtain gas (CUR)=25; Ion source gas 1 (GS1)=60;ion source gas 2 (GS2)=60; Ion spray Voltage (IS)=5500; Temperature(TEM)=600; interface Heater (ihe)=on. During the mass spectrometeracquisition, eleven MRM transitions were monitored. All eleven MRMtransitions were used for data processing. The peak areas under eachcorresponding MRM transitions were summed and compared to that of spikedstandard plasma samples to calculated concentration for each sample. Aquadratic (1/×) fitting was used for all calculations.

Anesthesia

Animals were induced with Telazol intramuscular and maintained withisoflurane on a ventilator.

Blood Sample Collection for Pharmacokinetic Studies

Blood samples were collected from one or more of the following bloodvessels in the animals: marginal ear veins/artery (left/right),saphenous veins (left/right), mammary veins (left/right), and femoralartery (left/right). Indwelling catheters/sheaths were placed to accessthe preferred blood vessel and were secured in place for the duration ofthe blood collection period. All procedures were performed by trainedstaff per approved protocols and SOPs at the Testing Facilities. A 5-mLblank blood collection was obtained from each animal prior to the firstdosing. One-mL blood samples were collected up to 5 hours after patchapplication dosing. Heparinized microtainer tubes were used to collectall blood samples. Blood volume drawn was replaced with equal volume ofheparinized saline with catheter's dead volume accounted. In general,blood collection on a daily basis did not exceed 3-5% of the animal'stotal blood volume.

Intravenous Dosing of Zolmitriptan

Zolmitriptan solution for IV dosing was prepared in-house with maximumzolmitriptan concentration of 3 mg/mL. Less than 3 mL of dosing volumewas injected using a 28-30 G needle into a marginal ear vein of theanimal. Pressure was applied momentarily with gauze immediately afterinjection to prevent bleeding at the site of injection.

Determination of Patch Delivery Performance ZP-Zolmitriptan DeliveryDetermination Using Residual Drug Analysis

Zolmitriptan residual was determined from the used patch and swabbingfrom the treated skin site. Once peeled off the skin, the used patcheswere trimmed of the adhesive band outside the microprojection array areaand saved for zolmitriptan residual analysis. To recover residualzolmitriptan from the treated skin site, three synthetic fiber swabswere used. The first swab was pre-wetted by insertion into a vialcontaining 1 mL of swab buffer. The first swab was applied over thepatch treatment skin site with slight pressure (using rolling motion) inseveral directions and up to the periphery of the treatment site. Thesecond and third swabs were dry and were used to capture all residualbuffer from the skin site that was wetted by the first swab. All threeswabs were placed in the original vial containing the swab buffer. Theamounts of zolmitriptan left on the microprojection array and skinsurface after each application were compared against the original coatedamounts on the array, allowing for the determinations of totalzolmitriptan Delivery and Delivery Efficiency. Equations to determinethe total drug delivered and drug delivery efficiency are shown below as(1) and (2) respectively.

$\begin{matrix}{{{Total}\mspace{14mu} {Residual}} = {{{Patch}\mspace{14mu} {Residual}} + {{Skin}\mspace{14mu} {Residual}}}} & \; \\{{{Total}\mspace{14mu} {Drug}\mspace{14mu} {Delivered}} = {{{Nominal}\mspace{14mu} {Coated}\mspace{14mu} {amount}} - {{Total}\mspace{14mu} {Residual}}}} & (1) \\{{{Delivery}\mspace{14mu} {Efficiency}\mspace{14mu} (\%)} = {\left( \frac{(1)}{{Nominal}\mspace{14mu} {Coated}\mspace{14mu} {amount}} \right)*100}} & (2)\end{matrix}$

Study Design

Three prepubescent female Yorkshire swine were used in the studies.Naïve animals were purchased from approved vendors per Test Facilities'approved protocol and SOPs and quarantined for up to 7 days. Each groupof animals was dosed up to 5 treatments (crossover) with arecovery/washout period of up to 5 days between treatments. At firstdosing, animals had weight ranging from 18-25 kg and at last dosing,animals had weights ranging from 25-41 kg. In general, treatments pergroup included one to two controls and one to three ZP-Zolmitriptandosing. Control included IV zolmitriptan. ZP-Zolmitriptan patchplacement was rotated from the left and right ventral thighs of the hindlimbs in each group of animals where more than one patch applicationtreatments were conducted.

Results

TABLE 31 In vivo Zolmitriptan patch delivery results Coated amount (mg)(SD) 1.89 (0.14) 2.02 ± 0.0.6 Mean Delivered amount (mg) (SD) 1.72(0.05) 1.79 (0.12) Mean Delivery Efficiency (%) 90.4 88.7 % CV 3 7 Minamount delivered (mg) 1.68 1.68 Max amount delivered (mg) 1.78 1.92 N 33

Mean delivery was >1.7 mg for all coated both in vivo studies. Deliveryefficiency were >85% and were consistent for both studies.Pharmacokinetic study was subsequently conducted with MF1663 arraydesign coated with 1.9 mg. Table 32 summarizes the patch and IV results.

TABLE 32 PK parameters of zolmitriptan patch in animal studies PKparameters IV ZP-Zolmitriptan Patch Coated Dose (mg) N/A 1.95 Dose(mg/Kg) 0.074 0.061 C_(max) (ng/mL) 251.7 ± 11.4  8.4 ± 1.7 (Mean ± SE)Median T_(max) (min) 1    15 (10-30) AUC_(t) (ng × h/mL) 27.4 ± 1.9 16.8± 1.5 (Mean ± SE) Absolute Bioavailability N/A 76.9 ± 8.2 (%) (Mean ±SE)

In vivo evaluation showed rapid systemic absorption of zolmitriptan withpatch administration. Plasma levels were maintained over 5 h with medianT_(max) of 15 minutes. Zolmitriptan patches had an absolutebioavailability of 77%. ZP-Zolmitriptan patch showed that the requisiteamount of drug could be coated, high delivery efficiency consistentlyattained and coated zolmitriptan was well absorbed with fast time toC_(max).

The study was repeated with a larger population of swine. Five animalswere treated with adhesive dermally-applied microarray (ADAM)zolmitriptan and 9 were administered with IV zolmitriptan. An additionalgroup of swine were tested with noncoated ADAM. The ADAM treatments wereapplied using a hand-held reusable applicator (total energy=0.26Joules). The ADAM patches were worn for an hour. The IV zolmitriptan wasapplied at a dose of 0.074 mg/kg body weight.

The microprojections for the ADAM microarray was 340 μm long. The depthof penetration (“DOP”) was measured for the microprojection penetrationsites. The mean DOP for ADAM zolmitriptan measured at 105.4±3.6 μm andfor noncoated ADAM was 123.9 4±4.8 μm. The DOP data indicated that mostmicroprojections penetrated about 50% or less of their length and thatDOP was reduced by approximately 15% in zolmitriptan-coatedmicroprojections relative to the noncoated ones. About 96.2% of the ADAMzolmitriptan-coated microprojections penetrated the dermis, and about11.4% of the DOP measurements showed penetrations deeper than 150μm—none beyond 300 μm. Epidermal-dermal junctions begin at 60 μm belowthe skin surface.

The ADAM Zolmitriptan application had a high efficiency despite the DOPdata indicating a depth of less than 50% of the microneedle's length.Mean residues on the worn ADAM were 10%, and on the treated skin sitesafter ADAM removal they were 5%. The bioavailability was 77%. The medianT_(max) for an ADAM Zolmitriptan of 1.9 mg was 15 minutes. Systematiczolmitriptan was detectable to the last sampling time point at 5 hoursfor ADAM Zolmitriptan and at 3 hours for IV Zolmitriptan.

PK Parameter IV Zolmitriptan ADAM Dose (mg/kg)  0.074 ± 0.001 0.060 ±0.004 AUC_(0-t), ng*h/mL 27.4 ± 1.9 16.8 ± 1.5  C_(max) 251.7 ± 11.4 8.4± 1.7 T_(max) — 15 (15-60) F (absolute — 77.3 ± 9.0  bioavailability), %Delivery efficiency —  85 ± 1.7

The bioavailaility along with the DOP data indicates that with ADAMadministration, 105 μm penetration depth (from the stratum corneum intothe dermis) may be sufficient to achieve optimal therapeutic outcome. Inaddition, ADAM intracutaneous delivery may circumvent first-passmetabolism. A preliminary analysis of the plasma PK samples forn-desmethyl metabolite indicated an average of 6.5% conversion from theparent compound.

After a 1-hour wear, zolmitriptan delivery was efficient, with only 15%of residual zolmitriptan on the skin and patch after removal. Evidenceof zolmitriptan diffusion within the skin was obtained by quantitativemass-specetrometry imaging. The zolmitriptan distribution is shown inthe table below. Analyses of the surface area of the stratum corneum,epidermis, and dermis indicate that the largest amount of zolmitriptanlocalized to the dermis. This suggests that most of the absorbedzolmitriptan had diffused past the epidermis into the dermal/hypodermalcapillary bed, as indicated by C_(max), within the 1 hour of ADAMZolmitriptan wear.

Percentage of Percentage of Total Skin Layers Total Surface AreaZolmitriptan Stratum corneum 1.2 1.8 Epidermis 3.8 2.7 Dermis/hypodermis95.0 95.5

Example 6—Human Efficacy Clinical Trial

The ZOTRIP pivotal efficacy study was a multicenter, double-blind,randomized, placebo-controlled trial comparing three doses of M207 (1.0mg, 1.9 mg, and 3.8 mg) to placebo for the treatment of a singlemigraine attack. Subjects were enrolled in the ZOTRIP trial at 36centers across the United States. Those recruited into the trial had ahistory of at least one year of migraine episodes with or without aura.Upon recruitment, the subjects entered a run-in period that ensured theymet the key eligibility criteria of 2-8 migraine attacks per month,which was documented using an electronic diary or an app on their cellphone. Subjects also identified their most bothersome other symptomselected from nausea, photophobia, and phonophobia, and indicated thepresence or absence of nausea, phonophobia or photophobia, during theepisodes in the run-in period. Successfully screened subjects were thenrandomized into the treatment/dosing period in which they had 8 weeks toconfirm and receive blinded treatment for a single migraine attack,termed “qualifying migraine,” in which their previously identified mostbothersome other symptom had to be present.

During a qualifying migraine, subjects scored the severity of pain onthe 4-point headache pain scale, and the presence or absence of migraineassociated symptoms (photophobia, phonophobia or nausea), startingpre-dose and then at several intervals over 48 hours post-dose. Theco-primary endpoints for the study were those defined in the October2014 FDA Draft Guidance—“Migraine: Developing Drugs for Acute Treatment”on pain and most bothersome other symptom freedom. Subjects recordedtheir migraine symptoms in a patient diary, prior to treatment, and atvarying intervals following treatment, out to 48 hours. Safety wasassessed by adverse events reported and other standard safety measures.

Five hundred and eighty nine (589) subjects were enrolled in this study,of which 365 were randomized. Of those randomized, 333 subjects weretreated and were included in the safety analysis, and 321 qualified forthe modified intent-to-treat (mITT) population. Fifty-one percent (51%)of the subjects randomized were found to have severe migraine painpre-treatment. Also at the time of treatment, 70% reported nausea, 37%aura, and 51% waking up with their migraine (morning migraine). With themultiple doses and multiple endpoints in the trial, a sequential testingprocedure was used beginning with the highest dose and the co-primaryendpoints. Since statistical significance was not achieved for mostbothersome other symptom in the 1.9 mg group, p-values for secondaryendpoints should be considered nominal p-values.

All three doses of M207 (1 mg, 1.9 mg, and 3.8 mg) achievedstatistically significant pain freedom at 2 hours. The 3.8 mg doseachieved both co-primary endpoints of pain freedom and most bothersomeother symptom freedom at 2 hours. The 3.8 mg dose also achievedsignificance in the secondary endpoints of pain freedom at 45 minutesand 1 hour and showed durability of effect on pain freedom at 24 and 48hours. Additionally, M207 was not associated with any Serious AdverseEvents (SAEs).

The 3.8 mg dose of M207 achieved statistical significance for bothco-primary endpoints at two hours, as shown in Table 33:

TABLE 33 Primary Endpoint Primary endpoint Placebo 3.8 mg M207 p-valuePain freedom 14.3% 41.5% 0.0001 Most bothersome other 42.9% 68.3% 0.0009symptom free

Furthermore, secondary endpoints measuring pain freedom at additionaltime points for the 3.8 mg dose of M207 showed M207 superior to placebowith a nominal p-value less than 0.05, as shown in Table 34:

TABLE 34 Pain Freedom Pain Freedom Placebo 3.8 mg M207 p-value* Painfreedom at 45 minutes 5.2% 17.1% 0.0175 Pain freedom at 60 minutes 10.4%26.8% 0.0084 Pain freedom at 24 hours 39.0% 69.5% 0.0001 Pain freedom at48 hours 39.0% 64.6% 0.0013

Overall, only 13 subjects (3.9%) reported pain at the application site;application site pain was reported as mild in all but three subjects.The most frequently reported adverse event was redness at theapplication site (18.3% of subjects). All cases of redness resolved.Further, five (1.5%) patients across M207-treated groups reporteddizziness vs. 0% on placebo.

Additional data from the results of the clinical trial are set forth inthe Tables below.

TABLE 35 Co-Primary Endpoints: Primary Endpoint Analysis Treatment GroupmITT Placebo 1 mg 1.9 mg 3.8 mg Population (LOCF) (N = 77) (N = 79) (N =83) (N = 82) Pain Freedom at 2 hours % (n/N) 14.3% 30.4% 27.7% 41.5%(11/77) (24/79) (23/83) (34/82) Difference from Placebo 16.1% 13.4%27.2% P-value 0.0149 0.0351 0.0001 Freedom from most bothersome othersymptom at 2 hours % (n/N) 42.9% 57.0% 53.0% 68.3% (33/77) (45/79)(44/83) (56/82) Difference from Placebo 14.1% 10.2% 25.4% P-value 0.07060.1694 0.0009

In Table 35, above, the 3.8 mg dose group met both co-primary endpointswith a p-value <0.05. The 1.9 mg dose group met the pain freedomendpoint with a p-value <0.05. For the freedom from most bothersomeother symptom at 2 hours endpoint, the 1.9 mg dose group had a p-valueof ≥0.05. The 1 mg dose group met the pain freedom endpoint with ap-value <0.05. For the 1 mg dose group, the freedom from most bothersomeother symptom endpoint at 2 hours had a p-value ≥0.05.

TABLE 36 Co-Primary Endpoints: Multiple Imputation Treatment Group mITTPlacebo 1 mg 1.9 mg 3.8 mg Population (LOCF) (N = 77) (N = 79) (N = 83)(N = 82) Pain Freedom at 2 hours Average % 14.7% 29.8% 29.4% 39.8%Difference from Placebo 15.1% 14.7% 25.1% P-value 0.0297 0.0344 0.0012Freedom from most bothersome other symptom at 2 hours % (n/N) 42.6%59.9% 56.5% 68.2% Difference from Placebo 17.3% 13.9% 25.6% P-value0.0294 0.0755 0.0013

Table 36, above, is consistent with co-primary endpoint analyses (mITTLOCF). Table 35, below, provides the fixed-sequence for testing each ofthe multiple endpoints that are described for migraines to assesswhether the study was successful. For doses of 3.8 mg, 1.9 mg, and 1.0mg, the efficacy of treatment was tested for the co-primary andsecondary endpoints in Table 35. As shown, all endpoints at or aftertesting order 4 are not significant under the MCP methodology.

TABLE 37 CP2016-001: MCP - Fixed Sequential Testing StatisticallyTesting Co-Primary/ significant Order Secondary Efficacy Endpoint DoseP-value Under MCP 1 co-primary Pain free at 2 hours 3.8 mg 0.0001 Yes 2co-primary Most bothersome other symptom free 3.8 mg 0.0009 Yes at 2hours 3 co-primary Pain free at 2 hours 1.9 mg 0.0351 Yes 4 co-primaryMost bothersome other symptom free 1.9 mg 0.1694 No at 2 hours 5secondary Pain relief at 30 minutes 3.8 mg 0.1024 No 6 secondary Painrelief at 30 minutes 1.9 mg 0.8642 No 7 secondary Pain relief at 2 hours3.8 mg 0.0013 No 8 secondary Pain relief at 2 hours 1.9 mg 0.1109 No 9co-primary Pain free at 2 hours 1.0 mg 0.0149 No 10 co-primary Mostbothersome other symptom free 1.0 mg 0.0706 No at 2 hours 11 secondaryPain relief at 30 minutes 1.0 mg 0.7839 No

Tables 38-46 provide results of a clinical study of treating with oneembodiment of the claimed invention. In this embodiment, as shown inTables 36-40, endpoints were evaluated sequentially, as described inTable 35, including pain freedom, pain relief, photophobia freedom,phonophobia freedom, and nausea freedom for treatment of 1 mg, 1.9 mg,and 3.8 mg at time points of 15 minutes, 30 minutes, 45 minutes, 1 hour,2 hours, 3 hours, 4 hours, 12 hours, 24 hours, and 48 hours aftertreatment. As shown in Tables 41-44, investigators also made visualassessments of the skin after patch removal for adverse events likebruising, edema, and erythema.

TABLE 38 Pain Freedom Pain Freedom (mITT/LOCF) Treatment GroupTime-point Placebo 1 mg 1.9 mg 3.8 mg 15 Minutes   0%   0%   0%   0% 30minutes  2.6% 2.5% 3.6% 7.3% 45 minutes  5.2% 3.8% 13.3%  17.1%*  1 hour10.4% 17.7%  20.5%  26.8%*  2 hour 14.3% 30.4%* 27.7%* 41.5%*  3 hour26.0% 40.5%* 37.3%  51.2%*  4 hour 28.6% 45.6%* 47.0%* 54.9%* 12 hours32.5% 54.4%* 53.0%* 62.2%* 24 hours 39.0% 59.5%* 61.4%* 69.5%* 48 hours39.0% 63.3%* 66.3%* 64.6%* *Indicates p-value < 0.05 however notsignificant under MCP

TABLE 39 Pain Relief Pain Relief (mITT/LOCF) Treatment Group Time-pointPlacebo 1 mg 1.9 mg 3.8 mg 15 Minutes 14.3% 12.7% 16.9% 23.2% 30 minutes33.8% 31.6% 32.5% 46.3% 45 minutes 45.5% 44.3% 45.8% 56.1%  1 hour 53.2%46.8% 55.4% 68.3%*  2 hour 57.1% 65.8% 68.7% 80.5%*  3 hour 51.9% 75.9%*66.3% 81.7%*  4 hour 51.9% 73.4%* 72.3%* 82.9%* 12 hours 48.1% 75.9%*72.3%* 80.5%* 24 hours 46.8% 72.2%* 72.3%* 78.0%* 48 hours 41.6% 72.2%*71.1%* 70.7%* *Indicates p-value < 0.05; however not significant underMCP

TABLE 40 Photophobia Freedom Pain Freedom (mITT/LOCF) Treatment GroupTime-point Placebo 1 mg 1.9 mg 3.8 mg 15 Minutes 9.1% 11.4% 9.6% 11.0%30 minutes 22.1% 27.8% 24.1% 26.8% 45 minutes 24.7% 43.0%* 33.7% 41.5%* 1 hour 33.8% 48.1%* 44.6% 53.7%*  2 hour 41.6% 60.8%* 56.6%* 69.5%*  3hour 44.2% 65.8%* 61.4%* 72.0%*  4 hour 45.5% 65.8%* 63.9%* 74.4%* 12hours 42.9% 74.7%* 66.3%* 75.6%* 24 hours 42.9% 72.2%* 68.7%* 73.2%* 48hours 40.3% 70.9%* 67.5%* 68.3%* *Indicates p-value < 0.05; however notsignificant under MCP

TABLE 41 Phonophobia Freedom Pain Freedom (mITT/LOCF) Treatment GroupTime-point Placebo 1 mg 1.9 mg 3.8 mg 15 Minutes 14.3% 20.3% 15.7% 25.6%30 minutes 35.1% 34.2% 28.9% 45.1% 45 minutes 37.7% 44.3% 43.4% 57.3%* 1 hour 46.8% 48.1% 57.8% 61.0%  2 hour 55.8% 58.2% 61.4% 69.5%  3 hour54.5% 63.3% 71.1%* 73.2%*  4 hour 57.1% 69.6% 69.9% 74.4%* 12 hours44.2% 73.4%* 68.7%* 78.0%* 24 hours 42.9% 69.6%* 68.7%* 76.8%* 48 hours42.9% 72.2%* 68.7%* 70.7%* *Indicates p-value < 0.05; however notsignificant under MCP

TABLE 42 Nausea Freedom Nausea Freedom (mITT/LOCF) Treatment GroupTime-point Placebo 1 mg 1.9 mg 3.8 mg 15 Minutes 36.4% 39.2% 41.0% 32.9%30 minutes 59.7% 55.7% 49.4% 53.7% 45 minutes 63.6% 58.2% 66.3% 62.2%  1hour 63.6% 68.4% 71.1% 76.8%  2 hour 63.6% 75.9% 74.7% 81.7%*  3 hour58.4% 78.5%* 74.7%* 79.3%*  4 hour 54.5% 78.5%* 73.5%* 79.3%* 12 hours45.5% 75.9%* 71.1%* 80.5%* 24 hours 44.2% 72.2%* 74.7%* 79.3%* 48 hours41.6% 72.2%* 72.3%* 70.7%* *Indicates p-value < 0.05; however notsignificant under MCP

TABLE 43 Investigator: Visual Dermal Assessment: PRSPB Treatment GroupPatch-Related Superficial Punctate Placebo 1 mg 1.9 mg 3.8 mg Bruising(PRSPB) (N = 83) (N = 78) (N = 84) (N = 83) None 82 (98.8%) 73 (93.6%)72 (85.7%) 74 (89.2%) <=25% ZP patch application site has 1 (1.2%) 5(6.4%)  9 (10.7%) 4 (4.8%) punctate bruising spots >=26% to < 50% ZPpatch application 0 (0.0%) 0 (0.0%) 2 (2.4%) 2 (2.4%) site has punctatebruising spots >50% ZP patch application site has 0 (0.0%) 0 (0.0%) 1(1.2%) 3 (3.6%) punctate bruising spots Note: Investigator assessmentoccurs at End-of Study; Day 2-8 (treatment on Day 1)

TABLE 44 Investigator: Visual Dermal Assessment: Edema Treatment GroupPlacebo 1 mg 1.9 mg 3.8 mg Edema (N = 83) (N = 78) (N = 84) (N = 83)None  83 (100.0%) 77 (98.7%) 81 (96.4%) 82 (98.8%) Slight 0 (0.0%) 1(1.3%) 3 (3.6%) 1 (1.2%) Edema Moderate 0 (0.0%) 0 (0.0%) 0 (0.0%) 0(0.0%) Edema Severe 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Edema Note:Investigator assessment occurs at Visit 4; End-of Study

TABLE 45 Investigator: Visual Dermal Assessment: Erythema TreatmentGroup Placebo 1 mg 1.9 mg 3.8 mg Erythema (N = 83) (N = 78) (N = 84) (N= 83) None 78 (94.0%) 71 (91.0%) 71 (84.5%) 64 (77.1%) Mild Redness 5(6.0%) 7 (9.0%) 10 (11.9%) 16 (19.3%) Well-defined 0 (0.0%) 0 (0.0%) 3(3.6%) 3 (3.6%) Redness Beet Redness 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)Note: Investigator assessment occurs at Visit 4; End-of Study

TABLE 46 General Disorders/Administration Disorders TEAEs System OrganClass/Preferred Treatment Group Term N (%) of Subjects Placebo 1 mg 1.9mg 3.8 mg General disorders and 12 (14.5%) 23 (28.8%) 31 (35.6%) 38(45.8%) administration site conditions Application site erythema 9(10.8%) 13 (16.3%) 17 (19.5%) 22 (26.5%) Application site bruise 3(3.6%) 5 (6.3%) 12 (13.8%) 12 (14.5%) Application site pain 1 (1.2%) 2(2.5%) 2 (2.3%) 8 (9.6%) Application site hemorrhage 0 (0.0%) 3 (3.8%) 5(5.7%) 4 (4.8%) Application site swelling 3 (3.6%) 1 (1.3%) 3 (3.4%) 2(2.4%) Application site edema 0 (0.0%) 1 (1.3%) 3 (3.4%) 2 (2.4%)Application site discoloration 1 (1.2%) 1 (1.3%) 1 (1.1%) 1 (1.2%) Note:TEAEs occurring in > 1 active treated subject

Tables 47-50 and FIGS. 25-28 demonstrate the efficacy of one embodimentof the claimed invention against published results of treatments thatare currently used in the art. Until the claimed invention, the state ofthe art included nasal treatments and standard and orally dissolvingtablets.

TABLE 47 Pain Free Zolmitriptan ZOLMITRIPTAN COMPARISON, % PAIN FREEDosage Form Dose 1 hour 2 hour 4 hour Reference M207 Patch 3.8 mg 26.8%41.5% 54.9% M207 Patch 1.9 mg 20.5% 27.7% 47.0% M207 Patch 1.0 mg 17.7%30.4% 45.6% NASAL 2.5 mg 10.6% 21.0% 38.4% Charlesworth et al, 2003TABLET 2.5 mg 10.4% 35.6% Pascual et al, 2000 TABLET   5 mg 10.0% 39.0%Dahlof et al 1998 TABLET  10 mg 9.0% 39.0% Dahlof et al 1998 ODT 2.5 mg7.8% 27.0% 37.0% Dowson et al, 2002 TABLET   5 mg 7.8% 29.3% 54.6%Geraud et al, 2000 TABLET 2.5 mg 5.7% 26.3% Steiner et al, 2003

TABLE 48 Pain Relief Zolmitriptan ZOLMITRIPTAN COMPARISON, % PAIN RELIEFDosage Form Dose 1 hour 2 hour 4 hour Reference M207 Patch 3.8 mg 68.3%80.5% 82.9% M207 Patch 1.9 mg 55.4% 68.7% 72.3% M207 Patch 1.0 mg 46.8%65.8% 73.4% ODT 2.5 mg 45.0% 63.0% Dowson et al, 2002 TABLET   5 mg44.0% 66.0% Dahlof et al 1998 NASAL 2.5 mg 40.2% 55.4% 63.4%Charlesworth et al, 2003 TABLET  10 mg 40.0% 71.0% Dahlof et al 1998TABLET 2.5 mg 35.3% 66.8% Pascual et al, 2000 TABLET   5 mg 34.2% 58.7%80.5% Geraud et al, 2000 TABLET 2.5 mg 25.1% 59.6% 25.1% Steiner et al,2003

TABLE 49 Pain Free Triptans COMPARISON TO OTHER TRIPTANS, % PAIN FREEDrug Dosage Form Dose 1 hour 2 hour 4 hour Reference Zolmitriptan ZSANPatch 3.8 mg 26.8% 41.5% 54.9% Zolmitriptan ZSAN Patch 1.9 mg 20.5%27.7% 47.0% Zolmitriptan ZSAN Patch 1.0 mg 17.7% 30.4% 45.6% RizatriptanWAFER 10 mg 13.0% 42.2% Ahrens et al, 1999 Zolmitriptan NASAL 2.5 mg10.6% 21.0% 38.4% Charlesworth et al, 2003 Rizatriptan TABLET 10 mg10.4% 40.3% Tfelt-Hansen et al, 1998 Eletriptan TABLET 80 mg 10.0% 27.0%49.0% Sheftell et al 2003 Zolmitriptan ODT 2.5 mg  7.8% 27.0% 37.0%Dowson et al, 2002 Zolmitriptan TABLET 5 mg  7.8% 29.3% 54.6% Geraud etal, 2000 Sumatriptan TABLET 100 mg  7.8% 32.8% Tfelt-Hansen et al, 1998Rizatriptan WAFER 5 mg  7.7% 34.8% Ahrens et al, 1999 Naratriptan TABLET2.5 mg  3.3% 20.7% Bomhof et al, 1999

TABLE 50 Pain Relief Triptans COMPARISON TO OTHER TRIPTANS, % PAINRELIEF Drug Dosage Form Dose 1 hour 2 hour 4 hour Reference ZolmitriptanZSAN Patch 3.8 mg 68.3% 80.5% 82.9% Zolmitriptan ZSAN Patch 1.9 mg 55.4%68.7% 72.3% Zolmitriptan ZSAN Patch 1.0 mg 46.8% 65.8% 73.4%Zolmitriptan ODT 2.5 mg 45.0% 63.0% Dowson et al, 2002 Rizatriptan WAFER10 mg 44.9% 74.1% Ahrens et al, 1999 Zolmitriptan NASAL 2.5 mg 40.2%55.4% 63.4% Charlesworth et al, 2003 Rizatriptan WAFER 5 mg 39.8% 58.6%Ahrens et al, 1999 Rizatriptan TABLET 10 mg 36.6% 67.0% Tfelt-Hansen etal, 1998 Zolmitriptan TABLET 5 mg 34.2% 58.7% 80.5% Geraud et al, 2000Eletriptan TABLET 80 mg 32.0% 59.0% 79.0% Sheftell et al 2003Sumatriptan TABLET 100 mg 27.9% 61.8% Tfelt-Hansen et al, 1998Naratriptan TABLET 2.5 mg 27.7% 48.4% Bomhof et al, 1999

The embodiments of the invention described above are intended to bemerely exemplary; numerous variations and modifications will be apparentto those skilled in the art. All such variations and modifications areintended to be within the scope of the present invention as defined inany appended claim.

We claim:
 1. An intracutaneous delivery system, comprising a pluralityof microprojections that are adapted to penetrate or pierce the stratumcorneum of a human patient, the microprojections having a solidformulation coating thereon covering about 10% to 80% of the length ofeach microprojection measured from the tip to the base, wherein thecoating comprises zolmitriptan or a pharmaceutically acceptable saltthereof in an amount of about 1 mg to about 5 mg per system, and whereinat least 95% of the zolmitriptan is released from the system withinabout 5 minutes when measured by USP Paddle Over Disk Method (Apparatus5).
 2. The system of claim 1 wherein at least 95% of the zolmitriptan isreleased within about 1 minute.
 3. The system of claim 1 wherein about100% of the zolmitriptan is released within about 1 minute.
 4. Thesystem of claim 1 wherein upon application of the system to a selectedarea of skin of the patient, the T_(max) of a therapeutically effectiveblood plasma concentration occurs within about 45 minutes of theapplication, the C_(max) is about 5 to about 25 ng/ml, and theAUC_(0-2 hr) is about 5 to about 20 ng/ml*hour.
 5. The system of claim 1wherein upon application of the system to a selected area of skin of thepatient, the T_(max) of a therapeutically effective serum concentrationoccurs within about 30 minutes of the application.
 6. The system ofclaim 1 wherein the formulation coating, before drying, has a viscosityof about 150 cP to about 350 cP and a surface tension of about 50 mNm⁻¹to about 72 mNm⁻¹.
 7. The system of claim 6 wherein the coating coversabout 20% to about 70% of the length of each microprojection.
 8. Thesystem of claim 7 wherein the coating covers about 30% to about 60% ofthe length of each microprojection.
 9. The system of claim 1 wherein theformulation coating, before drying, has a viscosity of about 200 cP toabout 300 cP and a surface tension of about 55 mNm⁻¹ to about 65 mNm⁻¹.10. The system of claim 1 wherein the formulation coating on eachmicroprojection has an approximate shape of an American football with athickness that tapers down from a maximum of about 270 μm.
 11. Thesystem of claim 10 wherein the microprojection is fabricated of a thinsheet of metal or a rigid material.
 12. The system of claim 10 whereinthe microprojection is fabricated of plastics or polymers.
 13. Thesystem of claim 10 wherein the microprojection is fabricated ofpolyetheretherketone (PEEK).
 14. A patch adhered to a substrate, whereinthe substrate comprises an array of microprojections that are coatedwith a formulation and wherein the patch has at least one of thefollowing features: a. a patch size selected from the group consistingof from about 1 to 20 cm², from about 2 to 15 cm², from about 4 to 11cm², about 5 cm², and about 10 cm²; b. a substrate size selected fromthe group consisting of from about 0.5 to 10 cm², from about 2 to 8 cm²,from about 3 to 6 cm², from about 3 cm², about 3.1 cm², about 3.13 cm²,and about 6 cm²; c. an array size selected from the group consisting offrom about 0.5 to 10 cm², from about 2 to 8 cm², from about 2.5 to 6cm², about 2.7 cm², about 5.5 cm², about 2.74 cm², and about 5.48 cm²;d. a density (microprojections/cm²) selected from the group consistingof at least about 10 microprojections/cm², from about 200 to 2000microprojections/cm², from about 500 to 1000 microprojections/cm², fromabout 650 to 800 microprojections/cm², and about 725microprojections/cm²; e. a number of microprojections/array selectedfrom the group consisting of from about 100 to 4000, from about 1000 to3000, from about 1500 to 2500, from about 1900 to 2100, about 2000,about 1987, from about 200 to 8000, from about 3000 to 5000, from about3500 to 4500, from about 4900 to 4100, about 4000, and about 3974; f. amicroprojection length selected from the group consisting of from about25 to 600 microns, from about 100 to 500 microns, from about 300 to 450microns, from about 320 to 410 microns, about 340 microns, about 390microns, about 387 microns, less than 1000 microns, less than 700microns, and less than 500 microns, wherein the microprojectionspenetrate the skin from about 25 to 1000 microns; g. a tip lengthselected from the group consisting of from about 100 to 250 microns,from about 130 to about 200 microns, from about 150 to 180 microns, fromabout 160 to 170 microns, and about 165 microns; h. a microprojectionwidth selected from the group consisting of from about 10 to 500microns, from about 50 to 300 microns, from about 75 to 200 microns,from about 90 to 160 microns, from about 250 to 400 microns, about 300microns, about 100 microns, about 110 microns, about 120 microns, about130 microns, about 140 microns, and about 150 microns; i. amicroprojection thickness selected from the group consisting of fromabout 1 micron to about 500 microns, from about 5 microns to 300microns, from about 10 microns to 100 microns, from about 10 microns to50 microns, from about 20 microns to 30 microns, and about 25 microns;j. a tip angle selected from the group consisting of about 10-70degrees, about 20-60 degrees, about 30 to 50 degrees, about 35 to 45degrees, and about 40 degrees; k. a total active agent per arrayselected from the group consisting of from about 0.1 mg to 10 mg, fromabout 0.5 mg to 5 mg, from about 1 mg to 4 mg, about 1 mg, about 1.9 mg,and about 3.8 mg; l. an amount of inactive ingredient per array selectedfrom the group consisting of from about 0.1 to 10 mg, from about 0.2 to4 mg, from about 0.3 mg to 2 mg, about 0.6 mg, about 0.63 mg, about 1.3mg, about 1.26 mg, from one to three times less than an active agent,and from about 0.033 mg to about 3.33 mg; m. a coating thicknessselected from the group consisting of from about 100 μm to about 500 μm,from about 200 μm to about 350 μm, from about 250 μm to about 290 μm,and about 270 μm; n. an active agent per microprojection selected fromthe group consisting of from about 0.001 to about 1000 μg, from about0.01 to about 100 μg, from about 0.1 to 10 μg, from about 0.5 to 2 μg,about 1 μg, and about 0.96 μg.
 15. The patch of claim 14 having a patcharea of about 5 cm² adhered to a titanium substrate with an area ofabout 3.1 cm² and a microprojection thickness of about 25 μm.
 16. Thepatch of claim 14, wherein the area of the microprojection array isabout 2.74 cm² and contains about 1987 microprojections at a density ofabout 725 microprojections/cm².
 17. The patch of claim 16, wherein theformulation contained on each microprojection has an approximate shapeof an American football with a thickness that tapers down from a maximumof about 270 μm, wherein the formulation comprises about 0.96 μs ofzolmitriptan and about 0.32 of tartaric acid, or about 1.9 mg ofzolmitriptan and about 0.63 mg of tartaric acid per patch.
 18. The patchof claim 14, having a patch area of about 5 cm² adhered to a titaniumsubstrate with an area of about 6 cm² to and a thickness of about 25 μm.19. The patch of claim 14, wherein the area of the microprojection arrayis about 5.5 cm² and contains about 4000 microprojections at a densityof about 725 microprojections/cm².
 20. The patch of claim 19, whereinthe formulation contained on each microprojection has an approximateshape of an American football with a thickness that tapers down from amaximum of about 270 μm and comprises about 0.96 μg of zolmitriptan andabout 0.32 of tartaric acid, or about 3.8 mg of zolmitriptan and about1.3 mg of tartaric acid per patch.
 21. The patch of claim 20, whereinmicroprojections have a length of about 387±13 μm, a width of about120±13 μm, and a thickness of about 25.4±2.5 μm.
 22. The patch of claim20, wherein microprojections are rectangular, with a triangular tip tofacilitate penetration and wherein the tip has an angle of 40±5 degrees,and a tip length of about 165±25 microns long.
 23. The patch of claim14, wherein the microprojections are bent at right angles to the planeof the substrate.
 24. The patch of claim 23, wherein themicroprojections: a. have a length of about 387±13 μm prior to bending,and b. protrude perpendicular to the substrate about 340 μm afterbending.
 25. The patch of claim 14, wherein the formulation does notcontain surfactants or other penetration enhancers.
 26. A method oftreating migraine or cluster headaches in a patient in need thereof,comprising applying the patch of claim 14 to a selected area of skin ofthe patient, wherein: a. the microprojections have a surface comprisinga solid coating formulation disposed thereon, wherein the coatingcomprises about 0.96 μg of zolmitriptan and about 0.32 of tartaric acid,about 1.9 mg of zolmitriptan and about 0.63 mg of tartaric acid, orabout 3.8 mg of zolmitriptan and about 1.3 mg of tartaric acid perpatch; b. the solid coating formulation does not contain surfactants orother penetration enhancers;
 27. The method of claim 26, wherein thesolid coating formulation is prepared by drying a liquid coatingformulation.
 28. The method of claim 27, wherein the liquid coatingformulation comprises: a. zolmitriptan in an amount selected from thegroup consisting of from 30% w/w to about 60% w/w, from about 40% w/w toabout 50% w/w, and about 45% w/w; b. tartaric acid in an amount selectedfrom the group consisting of from about 5% w/w to about 25% w/w, fromabout 10% w/w to about 20% w/w, and about 15% w/w; and c. a liquidcarrier.
 29. The method of claim 28, wherein the liquid carrier iswater.
 30. The method of claim 28, wherein the liquid coatingformulation has a viscosity selected from the group consisting of: lessthan about 500 centipoise (cP) and greater than about 3 cP, less thanabout 400 cP and greater than about 10 cP, less than about 300 cP andgreater than about 50 cP, less than about 250 cP and greater than about100 cP, more than about 80 cP and less than about 350 cP, more thanabout 100 cP and less than about 350 cP, more than about 100 cP and lessthan about 250 cP, at least 20 cP, at least about 25 cP, at least about30 cP, at least about 35 cP, at least about 40 cP, at least about 45 cP,at least about 50 cP, at least about 55 cP, at least about 60 cP, atleast about 65 cP, at least about 70 cP, at least about 75 cP, at leastabout 80 cP, at least about 85 cP, at least about 90 cP, at least about95 cP, at least about 100 cP, at least about 150 cP, at least about 200cP, at least about 300 cP, at least about 400 cP, and less than about500 cP, prior to coating.
 31. The method of claim 28, wherein the liquidcoating formulation has: a. a viscosity selected from the groupconsisting of from about 150 cP to about 350 cP, from about 200 cP toabout 300 cP, and about 250 centipoise; and b. a surface tensionselected from the group consisting of from about 50 mNm⁻¹ to about 72mNm⁻¹, from about 55 mNm⁻¹ to about 65 mNm⁻¹, and about 62.5 mNm⁻¹. 32.The method of claim 26, wherein the solid coating formulation has anaverage thickness selected from the group consisting of from about 10 toabout 400 microns, from about 30 to about 300 microns, from about 100microns to about 175 microns, from about 115 to about 150 microns, andabout 135 microns, as measured from the microprojection surface.
 33. Themethod of claim 32, wherein the solid coating formulation has a uniformthickness covering the microprojections.
 34. The method of claim 32,wherein the microprojection has a length, a base and a tip; and whereinthe solid coating formulation covers at least from about 10% to about80%, from about 20% to about 70%, from about 30% to about 60%, or fromabout 40% to about 50% of the length of the microprojection, as measuredfrom the tip to the base of the microprojection.
 35. A method fortreating cluster headache in a human patient, comprising the steps of:a. Providing an intracutaneous delivery system, comprising: i. adisposable patch assembly having a plurality of microprojectionsdisposed in an array of about 1 cm² to about 20 cm², the array having adensity of about 200 to about 2000 microprojections/cm², themicroprojections adapted to penetrate or pierce the stratum corneum of ahuman patient, ii. the microprojections having a solid formulationcoating disposed thereon, wherein the coating comprises zolmitriptan ora pharmaceutically acceptable salt thereof in an amount greater thanabout 0.1 mg/cm² to less than about 10 mg/cm², and iii. themicroprojections having a width of about 10 μm to about 500 μm and a tipangle of about 10 to about 70 degrees, and iv. wherein at least 95% ofthe zolmitriptan is released from the system within about 5 minutes whenmeasured by USP Paddle Over Disk Method (Apparatus 5); and b. applyingthe microprojections to a selected area of skin of the patient, whereinthe patient has pain freedom at about 15 or 30 minutes post-application,and wherein the T_(max) of a therapeutically effective blood plasmaconcentration of zolmitriptan occurs within about 30 minutes of theapplication, the C_(max) is less than about 50 ng/ml and theAUC_(0-2 hr) is about 5 to about 20 ng/ml*hour.
 36. The method of claim35 wherein the patient is free of one or more of the symptoms selectedfrom the group consisting of excruciating pain, restlessness, excessivetear production and redness in the eye on the affected side, stuffy orrunny nose, forehead or facial sweating, pale skin (pallor), facialflushing, swelling around the eye on the affected side, and droopingeyelid, at least 45 minutes post-a-application.
 37. The method of claim35 wherein the patient has pain freedom at about 15 or 30 minutespost-application.
 38. The method of claim 35 wherein the coating has athickness selected from the group consisting of from about 100 μm toabout 500 μm, from about 200 μm to about 350 μm, from about 250 μm toabout 290 μm, and about 270 μm.
 39. A method of treating clusterheadache in a population of human patients in need thereof, comprisingthe steps of: a. providing an intracutaneous delivery system,comprising: i. a disposable patch assembly having a plurality ofmicroprojections disposed in an array of about 0.5 to 10 cm², the arrayhaving a density of about 200 to about 2000 microprojections/cm², themicroprojections adapted to penetrate or pierce the stratum corneum of ahuman patient and having a length of about 25 μm to about 1000 μm, athickness of about 1 μm to about 500 μm, a width of about 10 μm to about500 μm, and are configured at a tip angle of about 10 to about 70degrees, ii. the microprojections having a solid formulation coatingdisposed thereon, wherein the coating comprises zolmitriptan or apharmaceutically acceptable salt thereof in an amount of from about 0.1mg to 10 mg per array, and iii. wherein at least 95% of the zolmitriptanis released from the system within about 5 minutes when measured by USPPaddle Over Disk Method (Apparatus 5); and b. applying themicroprojections to a selected area of skin of each patient, whereinmore than about 15% of the patients experience pain freedom at about 15or 30 minutes post-application, and wherein the T_(max) of atherapeutically effective blood plasma concentration of zolmitriptanoccurs within about 30 minutes of the application.
 40. The method ofclaim 39 wherein more than about 20% of the patients experience painfreedom at about 15 or 30 minutes post-application.
 41. The method ofclaim 39 wherein those patients experiencing pain freedom aresignificantly more by comparison to a second population of humanpatients who receive either conventional oral tablets of zolmitriptan ororally disintegrating tablets of zolmitriptan for treatment of clusterheadache.
 42. The patch of claim 14, wherein the active agent iszolmitriptan.
 43. The patch of claim 42, wherein zolmitriptan is presentin an amount of 1.9 mg, and wherein percutaneous absorption ofzolmitriptan through ex vivo human torso skin over 300 minutes from asingle application results in a mean flux of about 385±96 μg/cm²/hr at0.025 hr.
 44. The patch of claim 42, wherein zolmitriptan is present inan amount of 1.9 mg, and wherein percutaneous absorption of zolmitriptanthrough ex vivo human torso skin over 300 minutes from a singleapplication results in a mean flux of about 6.4±0.8 μg/cm²/hr at 4.75hr.
 45. The patch of claim 42, wherein total absorbed zolmitriptanthrough the skin to a receptor solution is about 83.4±1.3% for the 1.9mg patch.
 45. The patch of claim 42, wherein when zolmitriptan isapplied in a dose of 1.9 mg: a. peak flux occurred at approximately 4minutes after application with a peak flux of about 849±42 μg/cm²/hr;and b. a mass balance is about 90% of the applied dose.
 46. An adhesivedermally-applied microarray (ADAM) coated with zolmitriptan and appliedto a penetration site in a subject in need thereof, wherein: a. themicroarray comprises microprojections that are about 340 μm long, and b.mean depth of penetration in the penetration site is about 105.4±3.6 μmfrom stratum corneum into dermis layers of the penetration site.
 47. Thezolmitriptan-coated microarray of claim 46, wherein about 96% of themicroprojections penetrates the dermis.
 48. The zolmitriptan-coatedmicroarray of claim 46, wherein the microprojections penetrate onlyabout 50% or less of their length.
 49. The zolmitriptan-coatedmicroarray of claim 48, wherein mean residue of zolmitriptan on themicroarray is about 10% and on the penetration site after the removal ofthe microarray is about 5%.
 50. The zolmitriptan-coated microarray ofclaim 48, wherein median T_(max) for the zolmitriptan-coated microarrayof 1.9 mg of zolmitriptan is 15 minutes.